The role of PIK3CA mutations in the development of breast cancer (a literature review)
DOI:
https://doi.org/10.14739/2310-1210.2020.4.208402Keywords:
breast cancer, somatic mutations, PIK3CA gene, signaling cascade PI3K/AktAbstract
Today, breast cancer occupies a leading position in the structure of morbidity and mortality among women in Ukraineand and throughout the world. Late diagnosis of the disease adversely affects the prognosis. Since this pathology is characterized by a wide range of gene mutations, the relationship between the molecular genetic characteristics of a tumor and the prognostic and clinical characteristics of breast cancer is an extremely important issue. The PI3K/Akt signaling cascade is one of the key intracellular signaling pathways associated with the control of cell proliferation and regulation of potential oncogene protein kinase B/Akt functions. It can suppress apoptosis in different types of cancer, contributing to tumor cells survival. Also, mutations and amplification of the PI3K/Akt cascade components cause malignant cell transformation of various origin. The PIK3CA gene is one of the oncogenes, somatic mutations in which play an important role in the pathogenesis and progression of breast cancer. It encodes p110-α, the catalytic subunit of phosphatidylinositol-3-kinase-α. The most frequent mutation in PIK3CA gene is H1047R.
Conclusions. Numerous studies have shown that PIK3CA gene mutations in breast cancer patients have the potential to become a clinically important biomarker for improving the disease diagnosis and developing individualized targeted therapy. In this literature review we discuss the molecular mechanisms of PI3K signaling cascade activation and the role of PIK3CA mutations in the development of breast cancer.
References
(n.d.). PI3K: obshchie svedeniya [PI3K: general information]. Baza znanii po biologii cheloveka. http://humbio.ru/humbio/01122001/pi3k/0001095c.htm [in Russian].
Bondarenko, I. N., Elhajj, M. H., Prokhach, A. V., Zavizion, V. F., & Chebanov, K. O. (2016). Rak molochnoi zhelezy. Ot molekulyarnoi biologii k personifitsirovannoi terapii [Breast cancer. From molecular biology to personified therapy]. Morfolohiia, 10(1), 18-25. [in Russian].
Guda, B. B., Pushkarеv, V. M., Zhuravel, O. V., Pushkarеv, V. V., Kovalenko, A. Yе., Taraсhenko, Y. M., & Tronko, M. D. (2016). Ekspresiia ta aktyvatsiia proteinkinazy Akt/RKV v normalnykh tkanynakh, dobroiakisnykh ta vysokodyferentsiiovanykh zloiakisnykh pukhlynakh shchytopodibnoi zalozy liudyny [The expression and the activation of protein kinase Akt/PKB in normal tissues, benign and highly differentiated malignant human thyroid tumors]. Dopovidi NAN Ukrainy, (7), 120-124. https://doi.org/10.15407/dopovidi2016.07.120 [in Ukrainian].
Ostapchenko, L. I., Sinelnik, T. B., & Kompanets, I. V. (2016). Biolohichni membrany ta osnovy vnutrishnoklitynnoi syhnalizatsii. Teoretychni aspekty [Biological membranes and bases of intracellular signaling. Theoretical aspects]. Kyivskyi universytet. [in Ukrainian].
Fedorenko, Z. P., Hulak, L. O., Mykhailovych, Yu. Y., Horokh, Ye. L., Ryzhov, A. Yu., Sumkina, O. V., & Kutsenko, L. B. (2019). Rak v Ukraini, 2017 – 2018. Zakhvoriuvanist, smertnist, pokaznyky diialnosti onkolohichnoi sluzhby [Cancer in Ukraine, 2017 - 2018. Morbidity, mortality, indicators of the oncology service]. Biuleten natsionalnoho kantser-reiestru Ukrainy, (20). http://www.ncru.inf.ua/publications/BULL_20/index.htm [in Ukrainian].
Filipenko, M. L., Oskina, N. A., Oscorbin, I. P., Mishukova, O. V., Ovchinnikova, L. K., Ermilova, V. D., Gershtein, E. S., & Kushlinskii, N. E. (2016). Somaticheskie mutatsii gena PIK3CA v opukholyakh bol'nykh rakom molochnoi zhelezy [PIK3CA gene somatic mutations in the tumors of breast cancer patients]. Voprosy biologicheskoi, meditsinskoi i farmatsevticheskoi khimii, 19(12), 28-33. [in Russian].
Filipenko, M. L., Shamovskaya, D. V., Oskina, N. A., Oscorbin, I. P., Khrapov, E. A., Ovchinnikova, L. K., & Gershteyn, E. S. (2015). Razrabotka metoda vyyavleniya somaticheskikh mutatsii gena PIK3CA s pomoshch'yu mul'tipleksnoi allel'-spetsifichnoi PTsR v rezhime real'nogo vremeni i ego validatsiya v opukholyakh bol'nykh rakom molochnoi zhelezy [Development of a multiplex allele-specific real-time PCR method for detection of PIK3CA gene somatic mutations and its validation in the tumors of breast cancer patients]. Al'manakh klinicheskoi meditsiny, (41), 12-18. https://doi.org/10.18786/2072-0505-2015-41-12-18 [in Russian].
Tsukanov, K. Yu., Krasnenko, A. Yu., Korostin, D. O., Churov, A. V., Stetsenko, I. F., Plotnikov, N. A., Zarubina, S. A., Belova, V. A., Kovyrshina, A. V., Vorotnikov, I. K., Mescheryakov, A. A., & Ilyinsky, V. V. (2017). Rak molochnoi zhelezy: analiz spektra somaticheskikh draivernykh mutatsii s primeneniem vysokoproizvoditel'nogo sekvenirovaniya [Breast cancer: analysis of driver somatic mutations detected by next-generation sequencing]. Vestnik RGMU, (6), 52-58. [in Russian].
Markou, A., Farkona, S., Schiza, C., Efstathiou, T., Kounelis, S., Malamos, N., Georgoulias, V., & Lianidou, E. (2014). PIK3CA mutational status in circulating tumor cells can change during disease recurrence or progression in patients with breast cancer. Clinical Cancer Research, 20(22), 5823-5834. https://doi.org/10.1158/1078-0432.CCR-14-0149
Baselga, J., Im, S. A., Iwata, H., Cortés, J., De Laurentiis, M., Jiang, Z., Arteaga, C. L., Jonat, W., Clemons, M., Ito, Y., Awada, A., Chia, S., Jagiełło-Gruszfeld, A., Pistilli, B., Tseng, L. M., Hurvitz, S., Masuda, N., Takahashi, M., Vuylsteke, P., Hachemi, S., … Campone, M. (2017). Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology, 18(7), 904-916. https://doi.org/10.1016/S1470-2045(17)30376-5
Cantley, L. C. (2002). The Phosphoinositide 3-Kinase Pathway. Science, 296(5573), 1655-1657. https://doi.org/10.1126/science.296.5573.1655
Cosmic. (2019, September 5). COSMIC v91, released 07-APR-20. COSMIC. https://cancer.sanger.ac.uk/cosmic
Chopra, N., & Turner, N. C. (2017). Targeting PIK3CA-mutant advanced breast cancer in the clinical setting. The Lancet. Oncology, 18(7), 842-843. https://doi.org/10.1016/S1470-2045(17)30430-8
Cizkova, M., Susini, A., Vacher, S., Cizeron-Clairac, G., Andrieu, C., Driouch, K., Fourme, E., Lidereau, R., & Bièche, I. (2012). PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Research, 14(1), Article R28. https://doi.org/10.1186/bcr3113
Courtney, K. D., Corcoran, R. B., & Engelman, J. A. (2010). The PI3K pathway as drug target in human cancer. Journal of Clinical Oncology, 28(6), 1075-1083. https://doi.org/10.1200/JCO.2009.25.3641
Dumont, A. G., Dumont, S. N., & Trent, J. C. (2012). The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer. Chinese Journal of Cancer, 31(7), 327-334. https://doi.org/10.5732/cjc.012.10032
André, F., Ciruelos, E., Rubovszky, G., Campone, M., Loibl, S., Rugo, H. S., Iwata, H., Conte, P., Mayer, I. A., Kaufman, B., Yamashita, T., Lu, Y. S., Inoue, K., Takahashi, M., Pápai, Z., Longin, A. S., Mills, D., Wilke, C., Hirawat, S., Juric, D., … SOLAR-1 Study Group. (2019). Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. The New England Journal of Medicine, 380(20), 1929-1940. https://doi.org/10.1056/NEJMoa1813904
FDA. (2019, May 24). FDA approves first PI3K inhibitor for breast cancer. FDA. https://www.fda.gov/news-events/press-announcements/fda-approves-first-pi3k-inhibitor-breast-cancer
Filipenko, M. L., Os'kina, N. A., Oskorbin, I. A., Mishukova, O. V., Ovchinnikova, L. K., Gershtein, E. S., & Kushlinskii, N. E. (2017). Association between the Prevalence of Somatic Mutations in PIK3CA Gene in Tumors and Clinical and Morphological Characteristics of Breast Cancer Patients. Bulletin of Experimental Biology and Medicine, 163(2), 250-254. https://doi.org/10.1007/s10517-017-3777-z
Genatlas. (n.d.). PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide (3q26.32). Genatlas. http://genatlas.medecine.univ-paris5.fr/fiche.php?n=3220
Gkeka, P., Evangelidis, T., Pavlaki, M., Lazani, V., Christoforidis, S., Agianian, B., & Cournia, Z. (2014). Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant. PLoS Computational Biology, 10(10), Article e1003895. https://doi.org/10.1371/journal.pcbi.1003895
Gustin, J. P., Karakas, B., Weiss, M. B., Abukhdeir, A. M., Lauring, J., Garay, J. P., Cosgrove, D., Tamaki, A., Konishi, H., Konishi, Y., Mohseni, M., Wang, G., Rosen, D. M., Denmeade, S. R., Higgins, M. J., Vitolo, M. I., Bachman, K. E., & Park, B. H. (2009). Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2835-2840. https://doi.org/10.1073/pnas.0813351106
Wu, H., Wang, W., Du, J., Li, H., Wang, H., Huang, L., Xiang, H., Xie, J., Liu, X., Li, H., & Lin, W. (2019). The distinct clinicopathological and prognostic implications of PIK3CA mutations in breast cancer patients from Central China. Cancer Management and Research, 11, 1473-1492. https://doi.org/10.2147/CMAR.S195351
Juric, D., Krop, I., Ramanathan, R. K., Wilson, T. R., Ware, J. A., Sanabria Bohorquez, S. M., Savage, H. M., Sampath, D., Salphati, L., Lin, R. S., Jin, H., Parmar, H., Hsu, J. Y., Von Hoff, D. D., & Baselga, J. (2017). Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors. Cancer Discovery, 7(7), 704-715. https://doi.org/10.1158/2159-8290.CD-16-1080
Kalinsky, K., Jacks, L. M., Heguy, A., Patil, S., Drobnjak, M., Bhanot, U. K., Hedvat, C. V., Traina, T. A., Solit, D., Gerald, W., & Moynahan, M. E. (2009). PIK3CA mutation associates with improved outcome in breast cancer. Clinical Cancer Research, 15(16), 5049-5059. https://doi.org/10.1158/1078-0432.CCR-09-0632
Karakas, B., Bachman, K. E., & Park, B. H. (2006). Mutation of the PIK3CA oncogene in human cancers. British journal of cancer, 94(4), 455-459. https://doi.org/10.1038/sj.bjc.6602970
Kato, S., Iida, S., Higuchi, T., Ishikawa, T., Takagi, Y., Yasuno, M., Enomoto, M., Uetake, H., & Sugihara, K. (2007). PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. International Journal of Cancer, 121(8), 1771-1778. https://doi.org/10.1002/ijc.22890
Koboldt, D. C., Fulton, R. S., McLellan, M. D., Schmidt, H., Kalicki-Veizer, J., McMichael, J. F., Fulton, L. L., Dooling, D. J., Ding, L., Mardis, E. R., Wilson, R. K., Ally, A., Balasundaram, M., Butterfield, Y. S. N., Carlsen, R., Carter, C., Chu, A., Chuah, E., Chun, H.-J. E., … Palchik, J. D. (2012). Comprehensive molecular portraits of human breast tumours. Nature, 490(7418), 61-70. https://doi.org/10.1038/nature11412
Kodahl, A. R., Ehmsen, S., Pallisgaard, N., Jylling, A., Jensen, J. D., Laenkholm, A. V., Knoop, A. S., & Ditzel, H. J. (2018). Correlation between circulating cell-free PIK3CA tumor DNA levels and treatment response in patients with PIK3CA-mutated metastatic breast cancer. Molecular Oncology, 12(6), 925-935. https://doi.org/10.1002/1878-0261.12305
Kozaki, K., Imoto, I., Pimkhaokham, A., Hasegawa, S., Tsuda, H., Omura, K., & Inazawa, J. (2006). PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma. Cancer Science, 97(12), 1351-1358. https://doi.org/10.1111/j.1349-7006.2006.00343.x
Kumar, A., Rajendran, V., Sethumadhavan, R., & Purohit, R. (2013). AKT kinase pathway: a leading target in cancer research. The Scientific World Journal, 2013, Article 756134. https://doi.org/10.1155/2013/756134
WHO. (2018, September 12). Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018 [Press release]. https://www.who.int/cancer/PRGlobocanFinal.pdf
Lee, J. W., Soung, Y. H., Kim, S. Y., Lee, H. W., Park, W. S., Nam, S. W., Kim, S. H., Lee, J. Y., Yoo, N. J., & Lee, S. H. (2005). PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene, 24(8), 1477-1480. https://doi.org/10.1038/sj.onc.1208304
Liu, P., Cheng, H., Roberts, T. M., & Zhao, J. J. (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Reviews Drug Discovery, 8(8), 627-644. https://doi.org/10.1038/nrd2926
Luo, J., Manning, B. D., & Cantley, L. C. (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell, 4(4), 257-262. https://doi.org/10.1016/s1535-6108(03)00248-4
Mayer, I. A., Abramson, V. G., Formisano, L., Balko, J. M., Estrada, M. V., Sanders, M. E., Juric, D., Solit, D., Berger, M. F., Won, H. H., Li, Y., Cantley, L. C., Winer, E., & Arteaga, C. L. (2017). A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clinical Cancer Research, 23(1), 26-34. https://doi.org/10.1158/1078-0432.CCR-16-0134
Michelucci, A., Di Cristofano, C., Lami, A., Collecchi, P., Caligo, A., Decarli, N., Leopizzi, M., Aretini, P., Bertacca, G., Porta, R. P., Ricci, S., Della Rocca, C., Stanta, G., Bevilacqua, G., & Cavazzana, A. (2009). PIK3CA in breast carcinoma: a mutational analysis of sporadic and hereditary cases. Diagnostic Molecular Pathology, 18(4), 200-205. https://doi.org/10.1097/PDM.0b013e31818e5fa4
Mukohara, T. (2015). PI3K mutations in breast cancer: prognostic and therapeutic implications. Breast Cancer: Targets and Therapy, 7, 111-123. https://doi.org/10.2147/BCTT.S60696
Quinn, M., & Uk Statistics Authority. (2005). Cancer atlas of the United Kingdom and Ireland, 1991-2000. Palgrave Macmillan.
Saal, L. H., Holm, K., Maurer, M., Memeo, L., Su, T., Wang, X., Yu, J. S., Malmström, P. O., Mansukhani, M., Enoksson, J., Hibshoosh, H., Borg, A., & Parsons, R. (2005). PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Research, 65(7), 2554-2559. https://doi.org/10.1158/0008-5472-CAN-04-3913
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A., Powell, S. M., Riggins, G. J., Willson, J. K., Markowitz, S., Kinzler, K. W., Vogelstein, B., & Velculescu, V. E. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science, 304(5670), 554. https://doi.org/10.1126/science.1096502
Al-Sukhun, S., Lataifeh, I., & Al-Sukhun, R. (2016). Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data. Current Breast Cancer Reports, 8(2), 73-79. https://doi.org/10.1007/s12609-016-0215-6
Takeshita, T., Yamamoto, Y., Yamamoto-Ibusuki, M., Inao, T., Sueta, A., Fujiwara, S., Omoto, Y., & Iwase, H. (2015). Prognostic role of PIK3CA mutations of cell-free DNA in early-stage triple negative breast cancer. Cancer Science, 106(11), 1582-1589. https://doi.org/10.1111/cas.12813
Volinia, S., Hiles, I., Ormondroyd, E., Nizetic, D., Antonacci, R., Rocchi, M., & Waterfield, M. D. (1994). Molecular cloning, cDNA sequence, and chromosomal localization of the human phosphatidylinositol 3-kinase p110 alpha (PIK3CA) gene. Genomics, 24(3), 472-477. https://doi.org/10.1006/geno.1994.1655
Yi, Z., Ma, F., Li, C., Chen, R., Yuan, L., Sun, X., Guan, X., Li, L., Liu, B., Guan, Y., Qian, H., & Xu, B. (2017). Landscape of somatic mutations in different subtypes of advanced breast cancer with circulating tumor DNA analysis. Scientific Reports, 7(1), Article 5995. https://doi.org/10.1038/s41598-017-06327-4
Zhao, L., & Vogt, P. K. (2008). Class I PI3K in oncogenic cellular transformation. Oncogene, 27(41), 5486-5496. https://doi.org/10.1038/onc.2008.244
Zhao, W., Qiu, Y., & Kong, D. (2017). Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy. Acta Pharmaceutica Sinica B, 7(1), 27-37. https://doi.org/10.1016/j.apsb.2016.07.006
Downloads
How to Cite
Issue
Section
License
Authors who publish with this journal agree to the following terms:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access)
