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Volume 7, Issue 4 (July & August 2022)                   J Obstet Gynecol Cancer Res 2022, 7(4): 258-271 | Back to browse issues page


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Rahimi M, Talebi Kakroodi S, Tajvidi M. The Importance of RTK Signaling Genes and their Inhibitors in Breast Cancer. J Obstet Gynecol Cancer Res. 2022; 7 (4) :258-271
URL: http://jogcr.com/article-1-414-en.html
1- Department of Microbiology, Karaj Branch, Islamic Azad University, Karaj, Iran , mar.rahimi20@gmail.com
2- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
3- Clinical care and Health Promotion Research Center, Karaj Branch, Islamic Azad University, Karaj, Iran
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Introduction


Breast Cancer

The origin of breast cancer is breast tissue. This cancer is very a common cancer and the second cause of women’s death. Despite notable development in timely diagnosis and treatment over the past decades, breast cancer is still the leading cause of cancer death in women in several countries, especially in less developed countries (1).
Breast cancer usually starts from lobules and milk duct cells. It leads to lobular and ductal carcinomas. This cancer has about 18 subtypes (2).
Breast cancer risk factors are female gender, lack of physical exercise, obesity, hormone replacement therapy during menopause, drinking alcohol, first menstruation at an early age, ionizing radiation, family history, having children late in life or not having any, and older age (2, 3).
Recognizing clinical, biological, and pathological factors in Breast cancer can have mainly prognostic costs and factors that can use as a warning risk classification, treatment selection, and development of novel treatments (4).
In recent years, the importance of personalized medicine and other biomarkers has been emphasized, which may help explain the residual risk posed by traditional factors (4).
Most genes mutated in human cancers play a crucial role in the cell cycle, but most of them are involved in signal transduction. These signal transduction pathways are essential pathways through which cells communicate with their environment and play a pivotal role in regulating cell proliferation and death (5).
By inhibiting the genes of these pathways, the suppression of malignant tumors, such as breast cancer, could be possible. Better cancer treatments will hopefully be found by research and development in this field (6).
In about 5% of breast cancer, genetic factors have a more prominent role in developing hereditary breast-ovarian cancer syndromes, such as people with BRCA1 and BRCA2 gene mutations (7). These mutations cause 90% of the total genetic impact with a 60%-80% risk of breast cancer in people. Other cancers such as Li–Fraumeni syndrome (p53 gene mutation), Cowden syndrome (PTEN gene mutation), and Peutz–Jeghers syndrome (STK11 gene mutation) are also some other examples (8).
In 2012, it was found that, genetically, there were four types of breast cancer. In each type, specific genetic changes led to different types of cancer (9).
Normal cells will no longer need cell apoptosis; until then, they are protected by many clusters of proteins and pathways, such as receptor tyrosine kinase (RTK)/mTOR and RAS/MEK/ERK pathways. Sometimes, genes in these conservative pathways mutate constantly and prevent cell apoptosis if it is no longer needed. This is one of the stages that cause cancer, along with other mutations. Generally, in the apoptosis process, the PTEN protein inhibits mTOR and RTK signaling. The gene in the PTEN protein is mutated in several breast cancers; thus, in the “on” position, the RTK/mTOR pathway is unchanged, and the cancer cell does not destroy itself (10).

RTK Signaling

In cancer development, RTK signaling is one of the critical signal transduction pathways. This pathway is vital in the cell processes, such as cell division, growth, survival, and angiogenesis (11, 12). KIT, PI3K, and AKT genes play critical roles in this pathway (11).
As a receptor, KIT functions in cell signal transduction in various cell types, such as cancer cells. Usually, KIT is activated by binding to the stem cell factor. This pathway activation is followed by activating several transcription factors regulating cell differentiation, apoptosis, proliferation, and angiogenesis (13, 14).
In humans, the KIT gene is located on chromosome 4q12, adjacent to the highly homologous PDGFRA gene (15, 16). Recent studies have shown that mutations and overexpression of its gene can lead to developing malignancies, such as gastrointestinal stromal tumors (GISTs), leukemia, and melanomas (17-22).
The PI3K gene is located on chromosome 3q26. It is a heterodimeric enzyme, and p110a is a catalytic subunit encoded by PI3K (23). 
Important mutations in this gene generally involve activating a central element of this signaling pathway and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit A (PIK3CA) involved in cell proliferation, survival, and growth (23). PI3K mutation has been reported in breast cancer subtypes (24). 
Several studies have been conducted on the association between mutation and expression of the PI3K gene and malignancies, such as breast cancer (25).
AKT is a serine/threonine-specific protein kinase that has an important role in several processes, such as apoptosis and cell proliferation. This gene is present downstream of KIT and PI3K genes.
It is associated with tumor cell survival, proliferation, and invasiveness. Also, activation of this gene is crucial in human cancers and tumor cells. Understanding the role of AKT and its pathways is crucial to find an appropriate method for cancer treatment (26, 27).
AKT has three isoforms, namely AKT1, AKT2, and AKT3. AKT1 is located on 14q32, AKT2 on 19q13, and AKT3 on 1q44.
AKT1 plays a crucial role in tumor development and angiogenesis. Although disruption of AKT1 in mice suppressed physiological angiogenesis, it increased angiogenesis and tumor growth related to matrix abnormalities in skin and blood vessels (28, 29).
AKT1 is involved in the KIT/PI3K/AKT pathway and other signaling pathways. AKT2 regulates other AKT isoforms under hypoxic conditions; therefore, it operates as a significant regulator of AKT activity. Hypoxia induces the expression of AKT2. The importance of AKT3 in proliferation, apoptosis, and tumor growth was examined next (30, 31).

KIT Gene Mutations and Expression in Breast Cancer

The KIT gene is approximately 89 kb and has 21 exons (32, 33).
Exons 1-9 of KIT encode an extracellular domain with five immunoglobulin-like loops, exon 10 encodes transmembrane domain, exon 11 encodes a juxtamembrane domain, and exons 13-21 encode a tyrosine kinase domain (Figure 1) (34).
Several KIT mutations have specific clinicopathologic values and differ in their sensitivity to the inhibitor. In GISTs, exon 11 (KIT JM) and exon 17 (KIT TK2) have the highest frequency. Less frequently, mutations are reported in KIT exons 2, 8, and 9 (extracellular domain) or exons 13 and 14 (KIT TK1) (35, 36).
Mutation of KIT sequences in the subtype of breast cancer has been reported. In general, KIT is positive in the normal ductal epithelial of the breast. However, breast carcinomas have been found with increased expression.


Figure 1. The KIT protein and its different domains (13)

Figure 1. The KIT protein and its different domains (13)

 

This finding has been observed in KIT messenger RNA (mRNA) expressions in benign breast tumors (such as cystic fibrosis) that may retain KIT expression by the high differentiation status of epithelial and other cell sources (37-39).
In a recent study, 27 out of 48 patients’ tissues (56%) increased KIT gene expression compared to normal tissues (40).
Another subset of tumors with myoepithelial-like components is adenoid cystic carcinoma of the breast, found as KIT positive (41).
KIT positivity is almost prevalent in ductal carcinomas, HER2-positive, ER/PR, high-grade, keratin-positive, and prognostically unfavorable tumors.
KIT expression was observed in several typical cell types, including melanocytes, gastrointestinal Cajal cells, germ cells, mast cells, hematopoietic stem cells, and epithelial cells, especially ductal epithelia of the breast subsets neurons (42-47). For study and diagnostic purposes, these tissues can be used as a positive control in immunohistochemistry (IHC) for KIT.
Accordingly, several studies have been conducted on the relationship between mutation types and overexpression in the KIT gene, but less frequent of these results have been significant.
A study on 348 cases revealed a relationship between enhancing copy numbers in exons 15 and 18 and overexpression in phyllodes tumors; 46% and 12% of the patients respectively showed an increase in expression and copy number of this gene (48).
In another research, one mutation in exon 11 was found in triple-negative breast cancer (TNBC) tumors, and its overexpression was found in them (49).
In another study on phyllodes tumors, 2 of 13 cases of KIT had exon 17 alterations and overexpression (50).
In another study, 9 of 29 cases with TNBC and 9 of 18 cases with non-TNBC enhanced copy numbers and overexpression (51). A recent study showed that 27% of patients enhanced copy numbers (52). Another study indicated that patients with increased exon 7 CNV were in stage 3. Also, 60% of cases in exon 17, 60% in exon 18, and nearly 67% in exon 19 with enhanced CNVs had a tumor size of 2-5 cm; these findings are significant (53).
In a research study, KIT gene mutations were determined as 3.44%, 5.17%, 5.17%, 3.44%, 3.44%, and 5.17%, respectively, in exons 8, 9, 11, 13, 15, and 17 in breast cancer. The frequency of all KIT mutations in these exons was 25.86% (54).
These mutations can be distinguished from the activating mutations reported in GISTs. Genetically, they can indicate variations in cancer tumors. Also, an increased KIT copy number has almost been seen in breast cancer, unlike other cancers (17, 18, 48, 55-61). Table 1 shows the classification of studies performed.


Table 1. KIT variations and expression in various breast cancer types

Type Overexpression CNV Exon mutation References
TNBC 31-85% 22-42% Exon: 11 (49,51,58,59)
Non-TNBC 7-50% 18-50%
Malignant 12-100% 46% Exons: 1,2,7,8,9,11,13,15,17,18,19,21 (40,52,53,54,56)
Ductal carcinoma 24-60% 28-50% Exons: 11,13,17 (58,59,60,61)
Phyllodes tumor 46% 12% Exons: 15,17,18 (48,50)


We believe that the pattern of expression, mutation, and copy number genes in breast cancer is different from other cancers. This phenomenon is due to different mechanisms by which cancers develop. However, the type of mutations and expression are useful in categorizing different cancer types and subtypes. This matter can be helpful in breast cancer treatment, especially TNBCs.

Kit Inhibitors

Several monoclonal and polyclonal antibodies against the kit have been produced and are available. In several cancers, such as leukemia and GISTs, tyrosine kinase inhibitors are crucial drugs (62, 63).
The novel kit tyrosine kinase inhibitor, named imatinib mesylate (Gleevec formerly known as STI571), has shown to be effective in the treatment of metastatic cancers and GISTs; this encourages researchers to investigate other possible KIT-induced tumors. Imatinib drug is an adenosine triphosphate (ATP) analog for inhibiting kit. This drug is used against chronic myeloid leukemia and GISTs (64).
Tumors with exon 11 mutations have a good response. Those with exon 9 mutations are associated with moderate response and inadequate response with wild-type sequences. Those with exon 17 mutations have an inadequate response because of primary resistance (65).
Reciprocally, overexpression of the KIT gene leads to tumors of KIT-dependent cell types, such as mast cells, Cajal cells (GISTs), and germ cells (66). 
Secondary resistance, such as the development of KIT gene amplification and KIT mutations, was also reported (67). 
Another tyrosine kinase inhibitor is sunitinib, a small-molecule tyrosine kinase inhibitor for imatinib-resistant patients (68).
Sorafenib is another drug investigated in combination with other drugs in breast cancer. The clinical efficacy and safety of these drugs are still being investigated in clinical trials and studies. For instance, sorafenib has limited efficacy as a single agent in breast cancer; thus, studies are ongoing to evaluate its use combined with other drugs. Dose decreasing is the critical problem when sorafenib is used with other drugs or endocrine therapy. Further research can help discover a suitable dose (69).
Ponatinib is a multi-kinase inhibitor, such as KIT, FGFR, and BCR-ABL, to treat leukemia (70, 71). Nevertheless, no studies have been conducted on the effect of this drug on the inhibition of the KIT gene in breast cancer.
Regorafenib is a multi-kinase inhibitor that sup-presses the activity of several tyrosine kinases involved in angiogenesis and oncogenesis, such as VEGFR, PDGFR, FGFR, BRAF, RET, and KIT (72). Table 2 shows the drugs of kit inhibitors.
Currently, almost all tumors are tested for KIT positivity as potential targets for treatment with kit inhibitors. However, mutations in KIT activation are rarely found, leading to less successful treatment, with the possible exception of some myeloid leukemias. Insufficient variation and reproduction of kit staining have been common problems, especially with polyclonal antiserums. This matter has led to significant heterogeneity in the data, which is currently challenging to adapt to tumors (Figure 2) (13, 73).

 Table 2. Drugs of kit inhibitors

Drug name Product name Groups References
Imatinib Gleevec Approved (64)
Sunitinib Sutent Approved (68)
Sorafenib Nexavar Approved (69)
Ponatinib Iclusig Approved (70,71)
Regorafenib Stivarga Approved (72)


Figure 2. RTK signaling genes and drug inhibitors (73) 
Figure 2. RTK signaling genes and drug inhibitors (73)

 

PI3K Gene Mutations and Expression in Breast Cancer

Overexpression of the PI3K gene can cause cell proliferation and develop cancer cells, and it can be used as a biomarker for breast cancer treatment (74). To date, several intracellular pathways have been identified, and PI3K has a crucial role in breast cancer development (75, 76). Mutation and overexpression of the PI3K gene can be discussed as a crucial target in breast cancer treatment (77). 
Oncogenic mutation in PI3K is estimated in two various functions: activating mutation in the PI3K gene and downregulation of the expression of PTEN. Mutation in PI3K can be considered a key targeted therapy in breast cancer. PI3K opens a new window for clinicians to treat breast cancer. Several studies have indicated that the prevalence of PI3K mutations in breast cancer is from 8% to 40% (75, 78).
One study showed that PI3K overexpression occurred in 24% of all tumor samples in breast carcinomas (79).
However, some studies have shown different results. For example, in a study, 54.5% of patients showed overexpression of the PI3K gene. It was shown that 20% and 17.5% of patients had mutations and CNV in the PI3K gene, respectively (52, 80). In contrast, another study showed a significant positive relationship between mutations and PI3K expression in breast cancer (81).
Other studies have reported that activating mutations in PI3K account for approximately 30% of breast cancers and more in ER-positive. In particular, in exons 9 and 20, 80% of PI3K mutations are found. These two exons encode the helical and kinase domains, and they are considered hot spots for mutations (82-84).
Also, in TNBC, PI3K interacted directly or indirectly with ER and ER phosphorylation (85, 86). Estrogen deprivation has been shown to reduce PI3K activity. PI3K is generally mutated positively in ER. Another study showed that PI3K mutation occurred in at least 41.3% of ER-positive tumors (87, 88).
It has been indicated that about 40% of PI3K mutations are ER-positive and HER2-negative in both metastatic and primary breast malignancies. PI3K/AKT activation can occur by attached HER signaling as a ligand (89).
Also, in TNBC, even though the mutation is at a low rate, the PI3K pathway activity by gene expression or protein array signatures is at a high level (90).
Another investigation showed that the proportion of PI3K mutations in HR-positive/HER2-negative is 42%, in HER2-positive is 31%, and in TNBC is 16% (91).
PI3K mutation was found in 28% of HR-positive/HER2-negative tumors and 10% of TNBCs (92).
PI3K mutation was 12.5% in the TNBC subgroup to 41.1% in the HR-positive/HER2-negative subgroup (93).
Another review study showed that the rate of PI3K mutation is 23%-33% in HER2-positive tumors and 8% in TNBC or basal-like TNBC (94).
 Activating PI3K mutation has been seen in 30%-50% of advanced ER-positive/HER2-negative breast cancers, but PI3K is low in ER-negative breast cancers (95).
In another study on exons 9 and 20, on the contrary, regarding the relationship between PI3K mutations and some clinical features, such as age, lymph node metastases, tumor size, ER status, and PR, p53 expression, and mutations in breast cancer, no significant results were reported (81).
We believe that differences between the present study and other studies are due to variations in samples. Table 3 shows the classification of studies performed.


Table 3. PI3K variations and expression in various breast cancer types

Type Overexpression CNV Exon mutation References
All types 24-54% 17% 8-80%  (52,75,77-81)
TNBC - - 8-16% (75,77-79,90-94)
ER-positive 86-100% - 30-50% (82-84,87-89,95)
HER2- positive - - 23-33% (91,92,94)
HER2- negative - - 28-70% (89,91-93,95)

PI3K Inhibitors

PI3K mutations can be considered as biomarkers and have been the main focus of developing cancer drugs. The first clinical trials of RTK pathway inhibitors are underway. PI3K mutation screening can be helpful in genetic tests for diagnosis and targeted therapeutics.
PI3K inhibitors have received a great deal of attention in the development of breast cancer drugs (96).
There are several PI3K inhibitors, such as sonolisib (PX-866; for solid tumors), perifosine (for colorectal cancers), idelalisib (for CML), copanlisib (BAY 80-6946), serabelisib (for hematologic cancers), duvelisib, alpelisib, umbralisib, taselisib, buparlisib, and endocrine therapies (96-104). Table 4 shows the drugs of PI3K inhibitors.


Table 4. Drugs of PI3K inhibitors

Drug name Product name Groups References
Idelalisib Zydelig Approved (96-104)
Perifosine KRX-0401 Phase III clinical trials (96-104)
Sonolisib PX-866 Phase III clinical trials (96-104)
Copanlisib BAY 80-6946 Approved (96-104)
Duvelisib Copiktra Approved (96-104)
Serabelisib INK1117 Phase I (96-104)
Alpelisib BYL719 Approved (96-104)
Umbralisib Ukoniq Approved (96-104)
Taselisib GDC-0032 Phase III clinical trials (96-104)
Buparlisib BKM120 Phase III clinical trials (96-104)

On the other hand, despite many kit inhibitors, such as imatinib, resistance is frequently observed (105); as a result, PI3K inhibitors can be helpful in RTK inhibiting.
An investigation showed that p110α isoform-selective inhibitors were highly potental for inhibiting PI3K mutant inhibitors and promising (106). PI3K mutations can lead to resistance to kinase inhibitors. Therefore, there are various molecular features for breast tumors that should be considered when making treatment decisions. If there is no PI3K mutation, we can estimate the clinical/preclinical effect for the treatment (107).
A drug that acts by inhibiting one or more PI3K enzymes, the PI3K inhibitor, is part of the RTK pathway leading to metabolism, growth control, and translation initiation. The inhibition of many components in this pathway may lead to tumor suppression. These drugs are examples of targeted cancer therapy (107). Further investigation may demonstrate the efficacy of these medicines in the treatment of breast cancer.

AKT Gene Mutations and Expression in Breast Cancer

Several studies have investigated the relationship between AKT overexpression and breast cancer, with inconsistent results (108).
Many studies have reported the relationship between AKT and prognosis of breast cancer, onset, metastasis, and hormone therapy resistance. Evaluation of the expression and activation of AKT isoform in breast cancer and AKT1 and AKT2 expression in all breast cancer cell lineages has been done; however, the luminal breast cancer subtype has a high frequency. Also, AKT3 expression is associated with the TNBC subtype (109).
AKT1 has a crucial role in the onset of breast cancer and tumor development. In contrast, AKT2, through the formation of metastases, has an essential role in breast cancer progression. AKT3 has a crucial role in TNBC and ER-negative breast cancer. AKT3 is a pro-proliferative, anti-metastatic, and pro-oncogenic factor (109).
Generally, AKT overexpression in cancer is related to a poor prognosis (110).
Another study showed that 33% to 40% of breast tumors have AKT mutation (111).
In 2016, it was demonstrated that 4% of tumors had a mutation in AKT, and 14% had overexpression of this gene (112).
One study showed that 2.6% to 3.8 % of mutations in AKT were HR-positive/luminal, and 0% were HER2-positive and TNBC or basal-like. Also, 2.8% of HR-positive/luminal tumors showed AKT amplification (92).
Increasing evidence suggests that in early-stage breast cancer, AKT is associated with a good prognosis in ER-positive and a poor prognosis in ER-negative. In node-positive breast cancer, AKT is identified as a predicted benefit of paclitaxel chemotherapy (113).
A study showed that 1.4% of all tumors, 2.6% of HR-positive tumors, 3.2% of ER-positive/PR-positive tumors, and 0% of TNBCs have AKT mutation (114).
In a study, 33% of cases showed overexpression of AKT, 33% had DCIS, and 38% had invasive cancer (115).
Overexpression of AKT was observed in 44% of HER2-positive tumors compared to 22% of HER2-negative tumors (116).
One study showed that the frequency of AKT1 expression was about 24% (116).
A microarray study on invasive breast cancer showed a positive correlation between AKT1 expression and ER and HER2 status, as well as an inverse relationship between AKT1 expression and metastatic, tumor stages, and nodal status (117, 118).
Immunohistochemical staining showed that 24% of tumors were associated with AKT1 and 4% with AKT2 (117).
In other breast cancer tissues, HER2 expression was associated with overexpression of AKT2, but not AKT1; also, AKT2 protein overexpression was found in a breast cancer cell line by ectopic expression HER2 (116).
Gene amplification of AKT2 was found in 3% of tumors in a breast cancer study (119).
Based on a study, an increase in the copy number gene of AKT2 was observed in 2.8% to 4% of breast cancer tumors. (117, 119).
In metastatic HER2-positive breast cancer, AKT1 and AKT2 overexpression levels were 12.2% and 35.1% (120).
In breast cancer tissue, AKT3 is overexpressed compared to the adjacent normal breast tissue (121). The findings of this study did not show a significant relationship between its expression and hormone status, but AKT3 was expressed in TNBCs (122, 123).
AKT3 is amplified in 28% of breast cancers, according to The Cancer Genome Atlas (TCGA) (124).
Based on TCGA, the importance of AKT3 in TNBC was the amplification of this gene in 14% of TNBCs and 3% of luminal breast cancers, and overexpression of mRNA was found in 21% of TNBCs and 2% of luminal breast cancers (125).
Also, the increased copy number of the AKT3 gene was seen in TNBC (126).
Table 5 shows a classification of studies performed.


Table 5. AKT variations and expression in various breast cancer types

Type Overexpression CNV Exon mutation References
All types 4-38% 2.8-28% 1.4-40% (110-112,114-117,119,121,124)
TNBC 21% 14% 0 (92,109,114,122,123,125,126)
ER-positive 76% - 3.2% (114)
HER2-positive 12.2-44% - 0% (92,116-118,120)
HER2-negative 22% - - (116-118)

Akt Inhibitors

Akt inhibitors can be helpful to treat cancers due to the Akt functions mentioned earlier. Several Akt inhibitors are currently in the clinical trial stage (127).
The findings obtained from the Akt inhibitor process were associated with adenosine triphosphate (ATP)-competitive factors with different approaches using allosteric sites to suppress a very structural similarity between Akt isoforms in the catalytic domain and regardable structural analogy to the cytoplasmic serine/threonine kinase family. This process resulted in finding inhibitors with higher specificity, decreased toxicity, and fewer side effects. The second-generation Akt inhibitors are chemically reactive using a Michael acceptance pattern to target the nucleophilic cysteines in the catalytic activation loop (128).
All of the major components of the RTK pathway, including Akt, are being studied in depth in order to develop targeted therapies (129).
In 2011, phase 1 of the MK-2206 study on advanced solid tumors was reported (130). Several phase II studies have also been conducted on numerous cancer types (131).
In 2013, the results of the AZD5363 phase I study in solid tumors were reported (132). Also, a study of AZD5363 with olaparib was reported in 2016 (133).
In another study, ipatasertib is in phase II trials for TNBC (134).
Triciribine (TCN) or triciribine phosphate (TCN-P) monotherapy is used for solid tumors, such as breast cancer. However, clinical efficacy is limited due to toxicity (135).
GSK2110183 (afuresertib) is an orally available ATP-competitive and pan-AKT kinase inhibitor. It attenuated the phosphorylation levels of various Akt substrates (FOXO and caspase-9) in breast cancer (136). Table 6 shows the drugs of Akt inhibitors.
However, Akt inhibitors alone almost demonstrate limited clinical activity. Then, combinatorial treatments are helpful for Akt inhibitors.

 
Table 6. Drugs of Akt inhibitors

Drug name Product name Groups References
MK-2206 - Phase II clinical trials (130-131)
Capivasertib AZD5363 Phase I (132-133)
Ipatasertib PX-866 Phase II clinical trials (134)
Afuresertib GSK2110183 Phase I (136)


 

Conclusion

The findings revealed that KIT, PI3K, and AKT genes might have a role in cancer progression, especially in the development of sporadic breast cancer. These genes affect clinicopathological variables, such as angiogenesis (CD34), stage, grade, HER2, and ER. On the other hand, these genes alone can directly lead to the development of breast cancer because they start many critical pathways.
Studies have been conducted in some populations, such as Europe, Asia, America, etc., and the subtypes of different breast cancers.
Several tyrosine kinase inhibitors are currently used as drugs in other cancers to suppress these genes; accordingly, they can be used to treat and suppress the subtypes of different breast cancers, especially TNBC, with no common tissue markers in the future. Also, administering the inhibitors of these genes can suppress sporadic breast cancer.
Also, this matter is crucial that mutations in these pathway genes can cause resistance to tyrosine kinase drugs.
In this regard, more detailed studies are needed to confirm these findings and better understand and manage breast cancer patients.


 

Acknowledgments

The authors thank all those who helped them writing this article.

 

Conflicts of Interest

The authors declared no conflict of interest.
 

 
Systematic Review: Review | Subject: Gynecology Oncology
Received: 2021/06/6 | Accepted: 2021/07/24 | Published: 2022/03/14

References
1. Breast Cancer". NCI. Archived from the original on 25 June 2014. Retrieved 29 June 2014.
2. Breast Cancer Treatment. NCI. 23 May 2014. Archived from the original on 5 July 2014. Retrieved 29 June 2014.
3. World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.2.
4. Patani, N.,Martin, L.A.&Dowsett, M. Biomarkers for the clinical management of breast cancer: international perspective. Int J Cancer.2013; 133: 1-13. [DOI:10.1002/ijc.27997] [PMID]
5. Sever R, Brugge S. Signal Transduction in Cancer. Cold Spring Harbor Laboratory Press. 2017; 5(4): a006098. [DOI:10.1101/cshperspect.a006098] [PMID] [PMCID]
6. Shimizu K, Oku N. Cancer anti-angiogenic therapy. Biol Pharm Bull. 2004; 27: 599-605. [DOI:10.1248/bpb.27.599] [PMID]
7. Boris Pasche (2010). Cancer Genetics (Cancer Treatment and Research). Berlin: Springer. pp. 19-20. [DOI:10.1007/978-1-4419-6033-7] [PMID]
8. Gage M, Wattendorf D, Henry LR. Translational advances regarding hereditary breast cancer syndromes. Journal of surgical oncology.2012; 105 (5): 444-51. [DOI:10.1002/jso.21856] [PMID]
9. Kolata, Gina (23 September 2012). "Genetic Study Finds 4 Distinct Variations of Breast Cancer". The New York Times. Archived from the original on 24 September 2012. Retrieved 23 September 2012.
10. Adrian Lee; Carlos Arteaga (14 December 2009). "32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium". Sunday Morning Year-End Review. Archived from the original (PDF) on 13 August 2013.
11. King, D; Yeomanson, D; Bryant, HE. PI3King the Lock: Targeting the PI3K/Akt/mTOR Pathway as a Novel Therapeutic Strategy in Neuroblastoma. J Pediatr Hematol/Oncol. 2015;37(4): 245-51. [DOI:10.1097/MPH.0000000000000329] [PMID]
12. Peltier, J; O'Neill, A; Schaffer, D. V. PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol. 2007; 67(10): 1348-61 [DOI:10.1002/dneu.20506] [PMID]
13. Miettinen M, Lasota J. KIT (CD117): A Review on Expression in Normal and Neoplastic Tissues, and Mutations and Their Clinicopathologic Correlation. Appl Immunohistochem Mol Morphol. 2005; 13: 205-20. [DOI:10.1097/01.pai.0000173054.83414.22] [PMID]
14. Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924-31. [DOI:10.1007/s00018-004-4273-y] [PMID]
15. Yarden Y, Kuang WJ, Yang‐Feng T, Coussens L, Munemitsu S, Dull TJ, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand.EMBO J. 1987;6:3341-51. [DOI:10.1002/j.1460-2075.1987.tb02655.x] [PMID] [PMCID]
16. Spritz RA, Strunk KM, Lee ST, Lu-Kuo JM, Ward DC, Le Paslier D, et al. A YAC contig spanning a cluster of human type III receptor protein tyrosine kinase genes (PDGFRA-KIT-KDR) in chromosome segment 4q12. Genomics. 1994;22(2):431-6. [DOI:10.1006/geno.1994.1405] [PMID]
17. Tuveson D, Willis N, Jacks T, Gri J, Singer S. STI571 inactivation of the gastrointestinal stromal tumor c-KIToncoprotein: biological and clinical implications. Oncogene. 2001; 20:5054-8. [DOI:10.1038/sj.onc.1204704] [PMID]
18. Orsenigo M, Brich S, Riva C, Conca E, Bertulli R, Dileo P, et al. Fluorescence in situ hybridization analysis and immunophenotyping ofc-Kit/PDGFRA and Bcl-2 expression in gastrointestinal stromal tumors. Anal Quant CytolHistol. 2010; 32 (4):225-33.
19. Antonescu C, Romeo S, Zhang L, Nafa K, Hornick J, Nielsen G, et al. Dedifferentiation in Gastrointestinal Stromal Tumor to an Anaplastic KIT Negative Phenotype - a Diagnostic Pitfall. Morphologic and Molecular Characterization of 8 Cases Occurring either de-novo or after Imatinib Therapy. Am J Surg Pathol. 2013; 37(3): 385-92. [DOI:10.1097/PAS.0b013e31826c1761] [PMID] [PMCID]
20. Malaise M, Steinbach D, Corbacioglu S. Clinical implications of c-Kit mutations in acute myelogenous leukemia. Find out how to access preview-only content. Curr Hematol Malig Rep. 2009; 4(2): 77-82. [DOI:10.1007/s11899-009-0011-8] [PMID]
21. Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, Preudhomme C. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008; 22:915-31. [DOI:10.1038/leu.2008.19] [PMID]
22. Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, Town A, Harlow A. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14 (21):6821-8. [DOI:10.1158/1078-0432.CCR-08-0575] [PMID]
23. Entrez Gene: PIK3CA
24. Samuels Y, Waldman T. Rommel C, Vanhaesebroeck B, Vogt PK, eds. Oncogenic mutations of PIK3CA in human cancers. Current Topics in Microbiology and Immunology. Springer Berlin Heidelberg. 2010; 347: 21-41. [DOI:10.1007/82_2010_68] [PMID] [PMCID]
25. Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT. Discovery of colorectal cancer PIK3CA mutation as a potential predictive biomarker: power and promise of molecular pathological epidemiology. Oncogene. 2013; 33: 2949-55. [DOI:10.1038/onc.2013.244] [PMID] [PMCID]
26. Tumor Genetics; AKT Function and Oncogenic Activity" (PDF). Scientific Report. Fox Chase Cancer Center. 2005. Archived from the original (PDF) on 2010-06-04. Retrieved 2013-01-23.
27. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011; 365 (7): 611-9 [DOI:10.1056/NEJMoa1104017] [PMID] [PMCID]
28. Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, et al. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nature Med.2005; 11 (11): 1188-96. [DOI:10.1038/nm1307] [PMID] [PMCID]
29. Somanath PR, Razorenova OV, Chen J, Byzova TV. Akt1 in endothelial cell and angiogenesis. Cell Cycle.2006; 5 (5): 512-8. [DOI:10.4161/cc.5.5.2538] [PMID] [PMCID]
30. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332(6035):1317-22. [DOI:10.1126/science.1199498] [PMID] [PMCID]
31. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 2011; 365(7): 611-9.
32. Vandenbark GR, DeCastro CM, Taylor H, Kaufman E. Cloning and structural analysis of the human c-kit gene. Oncogene. 1992;7:1259-66.
33. Giebel LB, Strunk KM, Holmes SA, Spritz RA. Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. Oncogene. 1992;7(11):2207-17.
34. Longley BJ, Reguera MJ, Ma Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk Res. 2001;25(7):571-6. [DOI:10.1016/S0145-2126(01)00028-5]
35. [35] Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924-31. [DOI:10.1007/s00018-004-4273-y] [PMID]
36. Miettinen M, Lasota J. Gastrointestinal stromal tumors: definition, occurrence, pathology, differential diagnosis, and molecular genetics. Pol J Pathol. 2003; 54:3-24.
37. Miettinen, Markku MD; Lasota, Jerzy MD. KIT (CD117): A Review on Expression in Normal and Neoplastic Tissues, and Mutations and Their Clinicopathologic Correlation. Appl Immunohistochem Molecular Morphol. 2005;13 (3): 205-20. [DOI:10.1097/01.pai.0000173054.83414.22] [PMID]
38. Natali PG, Nicotra MR, Sures I, Mottolese M, Botti C, Ullrich A. Breast cancer is associated with loss of the c-kit oncogene product. Int J Cancer.1992; 52:713-7. [DOI:10.1002/ijc.2910520508] [PMID]
39. Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S, Ogawa M. Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer. 1996;73(10):1233-6. [DOI:10.1038/bjc.1996.236] [PMID] [PMCID]
40. M, Behjati F, Khorram Khorshid HR, Karimlou M, Keyhani E. The Relationship between KIT Copy Number Variation, Protein Expression, and Angiogenesis in Sporadic Breast Cancer. Rep Biochem Mol Biol. 2020; 9(1): 40-9. [DOI:10.29252/rbmb.9.1.40] [PMID] [PMCID]
41. Hill PA. c-kit expression in adenoid cystic carcinoma of the breast. Pathology. 2004; 36:362-4. [DOI:10.1080/00313020410001721537] [PMID]
42. Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A. Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res. 1992;52(22):6139-43.
43. Matsuda R, Takahashi T, Nakamura S, Sekido Y, Nishida K, Seto M, Seito T, Sugiura T, Ariyoshi Y, Takahashi T, Ueda R. Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol. 1993;142(1):339.
44. Tsuura Y, Hiraki H, Watanabe K, Suzuki T, Igarashi S, Shimamura K, et al. Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Archiv. 1994;424(2):135-41. [DOI:10.1007/BF00193492] [PMID]
45. Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994;42(11):1417-25. [DOI:10.1177/42.11.7523489] [PMID]
46. Maeda HI, Yamagata A, Nishikawa S, Yoshinaga KA, Kobayashi SH, Nishi KA, Nishikawa S. Requirement of c-kit for development of intestinal pacemaker system. Development. 1992;116(2):369-75. [DOI:10.1242/dev.116.2.369] [PMID]
47. Hulzinga JD, Thuneberg L, Klüppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature. 1995;373(6512):347-9. [DOI:10.1038/373347a0] [PMID]
48. Liu J, Liu X, Feng X, Liu J, Lv S, Zhang W, Niu Y. C-kit overexpression correlates with KIT gene copy numbers increases in phyllodes tumors of the breast. Breast Cancer Res Treat. 2015;149(2):395-401. [DOI:10.1007/s10549-014-3214-1] [PMID]
49. Zhu Y, Wang Y, Guan B, Rao Q, Wang J, Ma H, et al. C-kit and PDGFRA gene mutations in triple negative breast cancer. Int J Clin Exp Pathol. 2014;7(7):4280..
50. Carvalho S, e Silva AO, Milanezi F, Ricardo S, Leitão D, Amendoeira I, Schmitt FC. c-KIT and PDGFRA in breast phyllodes tumours: overexpression without mutations?. J Clin Pathol. 2004;57(10):1075-9. [DOI:10.1136/jcp.2004.016378] [PMID] [PMCID]
51. Johansson I, Aaltonen KE, Ebbesson A, Grabau D, Wigerup C, Hedenfalk I, Rydén L. Increased gene copy number of KIT and VEGFR2 at 4q12 in primary breast cancer is related to an aggressive phenotype and impaired prognosis. Genes, Chromosomes Cancer. 2012;51(4):375-83. [DOI:10.1002/gcc.21922] [PMID]
52. Rahimi M, Behjat F, Taheri N, Hosseini S, Khorshid HR, Moghaddam FA, et al. Correlation between important genes of mTOR pathway (PI3K and KIT) in Iranian women with sporadic breast cancer. Med J I R Iran. 2018;32:135.. [DOI:10.14196/mjiri.32.135] [PMID] [PMCID]
53. Rahimi M, Keyhani E, Behjati F. The Relation between Exon Variations of KIT Gene and Clinical Pathological Factors of Breast Cancer. J Obstet Gynecol Cancer Res. 2020;5(4):137-48. [DOI:10.30699/jogcr.5.4.137]
54. Hussain SR, Naqvi H, Ahmed F, Babu SG, Bansal C, Mahdi F. Identification of the c-kit gene mutations in biopsy tissues of mammary gland carcinoma tumor. J Egypt Natl Canc Inst. 2012;24(2):97-103.. [DOI:10.1016/j.jnci.2011.10.003] [PMID]
55. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proceedings of the National Academy of Sciences. 2014;111(2):711-6. [DOI:10.1073/pnas.1310501111] [PMID] [PMCID]
56. Kondi-Pafiti A, Arkadopoulos N, Gennatas C, Michalaki V, Frangou-Plegmenou M, Chatzipantelis P. Expression of c-kit in common benign and malignant breast lesions. Tumori J. 2010;96(6):978-84. [DOI:10.1177/548.6519] [PMID]
57. McIntyre A, Summersgill B, Grygalewicz B, Gillis AJ, Stoop J, van Gurp RJ, Dennis N, Fisher C, Huddart R, Cooper C, Clark J, Oosterhuis JW, Looijenga LH, Shipley J. Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Res. 2005; 65 (18): 8085-9. [DOI:10.1158/0008-5472.CAN-05-0471] [PMID]
58. R Diallo, E Ting, O Gluz, A Herr, G Schütt, H Geddert, S Mohrmann, C-kit expression in high-risk breast cancer subgroup treated with high-dose or conventional dose-dense chemotherapy. Verh Dtsch Ges Pathol. 2006; 90:177-85.
59. Diallo R, Rody A, Jackisch C, Ting E, C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu. Hum Pathol. 2006;37(2):205-11. [DOI:10.1016/j.humpath.2005.10.015] [PMID]
60. Tsutsui S, Yasuda K, Suzuki K, Takeuchi H, Nishizaki T, Higashi H, Era S. A loss of c-kit expression is associated with an advanced stage and poor prognosis in breast cancer. Br J Cancer. 2006;94(12):1874-8. [DOI:10.1038/sj.bjc.6603183] [PMID] [PMCID]
61. Hussain SR, G. Babu S, Raza ST, Singh P, Screening of the c-kit gene missense mutation in invasive ductal carcinoma of breast among north Indian population, Mol Biol Rep.2012; 39:9139-44. [DOI:10.1007/s11033-012-1786-6] [PMID]
62. Poveda A, GarcíadelMuro X, Lopez Guerrero J, Martínez V , Romero I, Valverde C, et al. GEIS 2013 guidelines for gastrointestinal sarcomas (GIST).Cancer Chemother Pharmacol.2014; 74:883-98. [DOI:10.1007/s00280-014-2547-0] [PMID] [PMCID]
63. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol.2002; 20:1692-703. [DOI:10.1200/JCO.2002.20.6.1692] [PMID]
64. [64] Demetri GD, Von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New Eng J Med. 2002;347(7):472-80. [DOI:10.1056/NEJMoa020461] [PMID]
65. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22: 3813-25. [DOI:10.1200/JCO.2004.05.140] [PMID]
66. Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924-31. [DOI:10.1007/s00018-004-4273-y] [PMID]
67. Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005; 128:270-9. [DOI:10.1053/j.gastro.2004.11.020] [PMID]
68. C. Heinrich M, Marino-Enriquez A, Presnell A, S. Donsky R, Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors. Mol Cancer Ther. 2012; 11(8): 1770-80. [DOI:10.1158/1535-7163.MCT-12-0223] [PMID] [PMCID]
69. Bronte G, Andreis D, Bravaccini S, Maltoni R, Sorafenib for the treatment of breast cancer. Expert Opin Pharmacother. 2017;18(6):621-30. [DOI:10.1080/14656566.2017.1309024] [PMID]
70. Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutan. J Med Chem. 2010; 53 (12): 4701-19. [DOI:10.1021/jm100395q] [PMID]
71. Musumeci F, Greco C, Grossi G, Molinari A, Schenone S. Recent studies on ponatinib in cancers other than chronic myeloid leukemia. Cancers. 2018;10(11):430. [DOI:10.3390/cancers10110430] [PMID] [PMCID]
72. Mehta M, Griffith J, Panneerselvam J, Babu A, Regorafenib sensitizes human breast cancer cells to radiation by inhibiting multiple kinases and inducing DNA damage, Int J Radiat Biol. 2020; 2;1-12.
73. https://innovationessence.com/cancerous-disorders-targeted/ Doctors Treat Deadly Cancerous Disorders with Gene-Guided, Targeted Therapy: Posted on February 16, 2017.
74. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7: 606-19. [DOI:10.1038/nrg1879] [PMID]
75. Samuels Y,Wang Z, Bardelli A, Siliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304:554. [DOI:10.1126/science.1096502] [PMID]
76. Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005;5: 921-9. [DOI:10.1038/nrc1753] [PMID]
77. Klarenbeek S, van Miltenburg MH, Jonkers J. Genetically engineered mouse models of PI3K signaling in breast cancer. Mol Oncol. 2013;7(2):146-64. [DOI:10.1016/j.molonc.2013.02.003] [PMID] [PMCID]
78. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancer. Clin Cancer Res. 2005; 11:2875-8. [DOI:10.1158/1078-0432.CCR-04-2142] [PMID]
79. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC and Brugge JS: Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res.2005;65:10992-1000. [DOI:10.1158/0008-5472.CAN-05-2612] [PMID]
80. Hosseini S, Behjati F, Rahimi M, Taheri N. The relationship between PIK3CA Amplification and P110α Tissue Expression with CD34 Tissue Expression as an Angiogenesis Marker in Iranian Women with Sporadic Breast Cancer. Iran J Pathol.2018; 13(4):447-453.
81. Dirican E, Akkiprik M, Özer A. Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer. Tumor Biol. 2016;37 (6):7033-45. [DOI:10.1007/s13277-016-4924-2] [PMID]
82. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov.2009;8:627-44. [DOI:10.1038/nrd2926] [PMID] [PMCID]
83. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CAmutations correlate with hormone receptors, nodemetastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005; 65:2554-9. [DOI:10.1158/0008-5472-CAN-04-3913] [PMID]
84. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007;317: 239-42. [DOI:10.1126/science.1135394] [PMID]
85. Guo RX, Wei LH, Wang JL, Sun PM, Sun XL. Activation of phosphatidylinositol 3-kinase-protein kinase B (PI3K-PKB) induced by 17beta-estradiol in endometrial carcinoma cell (Ishikawa). Zhonghua fu Chan ke za zhi. 2004;39(7):469-73.
86. Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ.Ligand-dependent interaction of estrogen receptoralpha with members of the forkhead transcription factor family. J Biol Chem. 2001;276(36):33554-60. [DOI:10.1074/jbc.M105555200] [PMID]
87. Generali D, Fox SB, Brizzi MP, Allevi G, Bonardi S, Aguggini S, et al. Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer. Clin Cancer Res. 2008;14(9):2673-80. [DOI:10.1158/1078-0432.CCR-07-1046] [PMID]
88. Campbell M, Allen WE, Sawyer C, Vanhaesebroeck B, Trimble ER. Glucose-potentiated chemotaxis in human vascular smoothmuscle is dependent on cross-talk between the PI3K and MAPK signaling pathways. Circ Res. 2004;95(4):380-8. [DOI:10.1161/01.RES.0000138019.82184.5d] [PMID]
89. Miricescu D, Totan A, Stanescu-Spinu II, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR signaling pathway in breast cancer: From molecular landscape to clinical aspects. Int J Mol Sci. 2021;22(1):173. [DOI:10.3390/ijms22010173] [PMID] [PMCID]
90. Cancer Genom Atlas Network. http://cancergenome.nih.gov.Accessed 13 Sep 2012.
91. Martínez-Sáez O, Chic N, Pascual T, Adamo B, Vidal M, Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020; 22: 45. [DOI:10.1186/s13058-020-01284-9] [PMID] [PMCID]
92. Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol. 2019;30:iii47.. [DOI:10.1093/annonc/mdz100]
93. Cizkova M,, Susini A, Vacher S, Cizeron-Clairac G, PIK3CAmutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res. 2012;14(1): R28. [DOI:10.1186/bcr3113] [PMID] [PMCID]
94. Lee J, Loh K, Yap Y, PI3K/Akt/mTOR inhibitors in breast cancer, Cancer Biol Med. 2015;12:342-54.
95. Rusquec P, Blonz C, Frenel J, Campone M. Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer, Therapeutic Advances in Medical Oncology. Ther Adv Med Oncol. 2020;12:1758835920940939. [DOI:10.1177/1758835920940939] [PMID] [PMCID]
96. Hanusch C, Schneeweiss A, Loibl S, Untch M, Paepke S, Kümmel S, et al. Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment for patients with locally advanced or operable breast cancer receiving taxaneanthracycline containing chemotherapy-DAFNE (GBG-70). Clin Cancer Res. 2015;21(13):2924-31. [DOI:10.1158/1078-0432.CCR-14-2774] [PMID]
97. Druker BJ. Imatinib: a viewpoint by Brian J. Druker Drugs. 2001;61(12):1775-6. [DOI:10.2165/00003495-200161120-00009] [PMID]
98. Arteaga CL, Moulder SL, Yakes FM. HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol. 2002; 3(11):4-10. [DOI:10.1053/sonc.2002.34047] [PMID]
99. Wakeling AE. Epidermal growth factor receptor tyrosine kinase inhibitors. Curr Opin Pharmacol. 2002;2(4):382-7. [DOI:10.1016/S1471-4892(02)00183-2]
100. "FDA Approval for duvelisib (COPIKTRA, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)". US Food and Drug Administration. September 24, 2018.
101. Novel Agents Show Promise Against Endocrine-resistant Breast Cancer. July 2016
102. FDA approves first PI3K inhibitor for breast cancer". 2019-05-24.
103. FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma". U.S. Food and Drug Administration (FDA). 5 February 2021. Retrieved 5 February 2021. This article incorporates text from this source, which is in the public domain.
104. TG Therapeutics Announces FDA Accelerated Approval of Ukoniq (umbralisib)" (Press release). TG Therapeutics. 5 February 2021. Retrieved 5 February 2021 - via GlobeNewswire.
105. Motawi TM, Sadik NA, Fahim SA, Shouman SA. Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells. Chem Biol Interact. 2015; 233:147-56. [DOI:10.1016/j.cbi.2015.03.028] [PMID]
106. Zardavas D, Phillips WA, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res. 2014;16(1):201. [DOI:10.1186/bcr3605] [PMID] [PMCID]
107. Coughlin CM, Johnston DS, Strahs A, Burczynski ME, Bacus S, Hill J, et al. Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy. Breast Cancer Res Treat. 2010; 124:1-11. [DOI:10.1007/s10549-010-1108-4] [PMID]
108. Yang Z, Di M, Yuan J, Shen W, The prognostic value of phosphorylated Akt in breast cancer: a systematic review. Sci Rep.2015;5:7758. [DOI:10.1038/srep07758] [PMID] [PMCID]
109. Hinz N, Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Communication and Signaling. 2019;17(1):154. [DOI:10.1186/s12964-019-0450-3] [PMID] [PMCID]
110. Pérez-Tenorio G, Stål O. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002;86(4):540-5. [DOI:10.1038/sj.bjc.6600126] [PMID] [PMCID]
111. Liu W, Bagaitkar J, Watabe K, Roles of AKT signal in breast cancer. Front Biosci.2007; 12,4011-9. [DOI:10.2741/2367] [PMID]
112. Tserga A, Chatziandreou I, V. Michalopoulos N, Patsouris E. Mutation of genes of the PI3K/AKT pathway in breast cancer supports their potential importance as biomarker for breast cancer aggressiveness. Virchows Arch. 2016; 469:35-43. [DOI:10.1007/s00428-016-1938-5] [PMID]
113. Yang S, Polley E, Lipkowitzc S, New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat Rev.2016;45:87-96. [DOI:10.1016/j.ctrv.2016.03.004] [PMID] [PMCID]
114. Stemke-Hale K, Gonzalez-Angulo A, Lluch A, M. Neve R. An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer, Cancer Res.2008;68(15):6084-91. [DOI:10.1158/0008-5472.CAN-07-6854] [PMID] [PMCID]
115. A. Aleskandarany M, A. Rakha E, A. Ahmed M, G. Powe D, Clinicopathologic and molecular significance of phospho-Akt expression in early invasive breast cancer. Breast Cancer Res Treat.2011;127:407-16. [DOI:10.1007/s10549-010-1012-y] [PMID]
116. Altomare D, Testa J, Perturbations of the AKT signaling pathway in human cancer. Oncogene.2005;24: 7455-64. [DOI:10.1038/sj.onc.1209085] [PMID]
117. Stål O, Pérez-Tenorio G, Akerberg L, Olsson B, Nordenskjöld B, Skoog L, et al. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 2003;5(2): 37-44. [DOI:10.1186/bcr569] [PMID] [PMCID]
118. Florena AM, Tripodo C, Guarnotta C, Ingrao S, Porcasi R, Martorana A, et al. Associations between Notch-2, Akt-1 and HER2/neu expression in invasive human breast cancer: A tissue microarray immunophenotypic analysis on 98 patients. Pathobiology.2007;74(6):317-22. [DOI:10.1159/000110024] [PMID]
119. Bellacosa A. Feo Dd, Godwin AK, Bell DW, Cheng JQ, Altomare DA, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995;64(4):280-5. [DOI:10.1002/ijc.2910640412] [PMID]
120. Grell P, Fabian P, Khoylou M, Radova L, Slaby O, Hrstka R, et al. Akt expression and compartmentalization in prediction of clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Int J Oncol. 2012;41(4):1204-12 [DOI:10.3892/ijo.2012.1576] [PMID] [PMCID]
121. Hu X, Wang J, He W, Zhao P, Ye C. MicroRNA-433 targets AKT3 and inhibits cell proliferation and viability in breast cancer. Oncol Lett. 2018;15(3):3998-4004. [DOI:10.3892/ol.2018.7803] [PMID] [PMCID]
122. Pérez-Tenorio G, Karlsson E, Stål O. Clinical value of isoform-specific detection and targeting of AKT1, AKT2 and AKT3 in breast cancer. Breast Cancer Man. 2014;3(5):409-21. [DOI:10.2217/bmt.14.35]
123. Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, et al. AKT-1, −2, and −3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin Cancer Res. 2001;7(8):2475-9.
124. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70. [DOI:10.1038/nature11412] [PMID] [PMCID]
125. Chin YR, Yoshida T, Marusyk A, Beck AH, Polyak K, Toker A. Targeting Akt3 signaling in triple-negative breast cancer. Cancer Res. 2014;74(3):964-73. [DOI:10.1158/0008-5472.CAN-13-2175] [PMID] [PMCID]
126. O'Hurley G, Daly E, O'Grady A, Cummins R, Quinn C, Flanagan L, et al. Investigation of molecular alterations of AKT-3 in triple-negative breast cancer. Histopathology. 2014;64(5):660-70. [DOI:10.1111/his.12313] [PMID]
127. Vio Quest Pharmaceuticals Announces Phase I/IIa Trial For Akt Inhibitor VQD-002. Apr 2007.
128. NITULESCU GM, MARGINA D, JUZENAS P, PENG Q. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). Int J Oncol. 2016; 48(3): 869-85. [DOI:10.3892/ijo.2015.3306] [PMID] [PMCID]
129. Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des. 2010; 16:34-44. [DOI:10.2174/138161210789941865] [PMID]
130. [130] Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol.2011; 29(35): 4688-95. [DOI:10.1200/JCO.2011.35.5263] [PMID]
131. MK-2206 phase-2 trials.
132. AKT inhibitor AZD5363 well tolerated, yielded partial response in patients with advanced solid tumors.
133. "PARP/AKT Inhibitor Combination Active in Multiple Tumor Types. April 2016". Archived from the original on 2016-05-07. Retrieved 2016-04-20.
134. Jabbarzadeh Kaboli P, Salimian F, Aghapour S, Xiang S, Zhao Q, Li M, et al. Akt-targeted therapy as a promising strategy to overcome drug resistance in breast cancer - A comprehensive review from chemotherapy to immunotherapy". Pharmacol Res.2020;156:104806. [DOI:10.1016/j.phrs.2020.104806] [PMID]
135. Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ, et al. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ. 2010; 17:1795-804. [DOI:10.1038/cdd.2010.63] [PMID] [PMCID]
136. Song M, M. Bode A, Dong Z, Lee M. AKT as a Therapeutic Target for Cancer. Cancer Res.2019; ;79(6):1019-31. [DOI:10.1158/0008-5472.CAN-18-2738] [PMID]

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