Hülya YAZICI, Demet AKDENİZ, Şeref Buğra TUNÇER

PTEN Gen Yolağı ve Meme Kanseri Arasındaki İlişki

Dünya genelinde meme kanseri kadınlarda en yaygın görülen ve en yüksek mortalite oranına sahip kanserdir. Protein tirozin fosfotaz ve tensinhomoloğu (PTEN) geni hücre büyümesi, proliferasyon ve migrasyon gibi birçok hücresel fonksiyonu düzenleyen kromozomun 10q23 bölgesindelokalize tümör baskılayıcı bir gendir. PTEN gen mutasyonları ve somatik delesyonları meme kanseri de dahil birçok kanserde görülmektedir. Sporadikmeme kanserlerinin %5’inde PTEN mutasyonlarına rastlanmıştır. Ayrıca PTEN genindeki kalıtsal mutasyonlar Cowden hastalığı olarak bilinen ve tümyaşam boyunca meme kanseri gelişme riski %25-50 arasında olan nadir, otozomal dominant, ailesel kanser sendromları ile de ilişkilidir. Cowdensendromu taşıyan ailelerin %80’inde PTEN germline mutasyonları mevcuttur. 10q23 bölgesindeki yüksek heterozigot kaybı frekansı ve mutasyondurumu bulunmayan protein ekspresyon kaybı PTEN geninde başka inaktivasyon mekanizmalarının da etkili olduğu sonucunu desteklemektedir.Promotor bölge içindeki sitozin-guanin (CpG) bölgelerindeki hipermetilasyonlar gibi epigenetik olayların bu mekanizmalardan biri olabileceğidüşünülmüştür. PTEN, fosfatidilinositol 3-kinaz/protein kinaz B yolağını inhibe ederek hücre büyümesi ve hücre proliferasyonunu azaltır. PTENkaybı BRCA1 mutasyonlu meme kanserleri ile ilişkilidir ve homozigot delesyonlar, DNA çift zincir kırıklarını kapsayan genom instabilitesi ilesonuçlanabilir. PTEN’in DNA tamiri ve farklı dokulardaki DNA hasar tepkisinin anlaşılması PTEN’in genomik stabiliteyi dengelemesini sağlayanmoleküler mekanizmaların anlaşılmasını sağlayacaktır. Tümör baskılayıcı gen olan BRCA1 ve PTEN arasındaki bağlantının anlaşılması kansere karşıdaha iyi tedavi stratejilerinin oluşturulması ve etkili ajanların keşfedilmesine olanak sağlayacaktır. Bu derlemeyi hazırlamamızdaki temel amaç; PTENgeninin meme kanserindeki önemini vurgulamak ve PTEN yolağı ve bu yolağın diğer yolaklarla ilişkilerini açıklayarak meme kanserinde yeni hedef tedavilerin geliştirilmesidir.

Relationship Between PTEN Gene Pathway and Breast Cancer

Breast cancer is the most common malignancy with a high mortality in females worldwide. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located on chromosomal band 10q23 and regulates many cellular functions including cell growth, proliferation, and migration. Somatic deletions and/or mutations of PTEN gene is commonly seen in several cancers including breast cancer. PTEN mutations have been found in only 5% of sporadic breast cancers. Germline mutations of the PTEN gene are associated with a rare, autosomal-dominant, familial cancer syndrome known as Cowden disease, which is associated with a 25 to 50% lifetime risk of developing breast cancer. In families with Cowden sendrome, 80% have PTEN germline mutations. The high frequency of loss of heterozygosity in 10q23 and the loss of protein expression without a comparable mutational status suggest there should be other inactivation mechanisms of the PTEN gene. Epigenetic events, such as hypermethylation of cytosine-guanine (CpG) sites in the promoter region, could be one mechanism. PTEN inhibits the phosphatidylinositol 3-kinase/protein kinase B pathway, whose inhibition eventually reduces cell growth and cell proliferation. PTEN loss is highly associated with BRCA1 breast cancers, which could result from genome instability involving homozygous deletions, DNA double-strand breaks and so on. Further detailed mechanistic understanding of the roles of PTEN in DNA repair and DNA damage response in different tissues and cell types will help us fully understand the pre- cise molecular mechanisms by which PTEN maintains genomic stability and contributes to tumor suppression and therapeutic efficacy. Understanding the connection between tumor suppressor BRCA1 and PTEN would facilitate the development of effective agents and strategies to better treatment against cancer. The main purpose of our preparation of this review to emphasize the importance of PTEN gene in breast cancer and PTEN pathway and the development of new targeted therapies in breast cancer by explaining the relationship between this pathway and other pathways.

PDF

___

Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol 2001;14:672-676.
Inanc M, Ozkan M, Karaca H, et al. Cytokeratin 5/6, c-Met expressions, and PTEN loss prognostic indicators in triple-negative breast cancer. Med Oncol 2014;31:801.
Constantinou C, Papadopoulos S, Karyda E, et al. Expression and Clinical Significance of Claudin-7, PDL-1, PTEN, c-Kit, c-Met, c-Myc, ALK, CK5/6, CK17, p53, EGFR, Ki67, p63 in Triple-negative Breast Cancer-A Single Centre Prospective Observational Study. In Vivo 2018;32:303-311.
Rhei E, Kang L, Bogomolniy F, et al. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res 1997;57:3657-3659.
Zhang HY, Liang F, Jia ZL, et al. PTEN mutation, methylation and expression in breast cancer patients. Oncol Lett 2013;6:161-168.
Ghosh AK, Grigorieva I, Steele R, et al. PTEN transcriptionally modulates c-myc gene expression in human breast carcinoma cells and is involved in cell growth regulation. Gene 1999;235:85-91.
Xu F, Zhang C, Cui J, et al. The prognostic value and potential drug target of phosphatase and tensin homolog in breast cancer patients: A metaanalysis. Medicine (Baltimore) 2017;96:e8000.
Li S, Shen Y, Wang M, et al. Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis. Oncotarget 2017;8:32043-32054.
Kechagioglou P, Papi RM, Provatopoulou X, et al. Tumor suppressor PTEN in breast cancer: heterozygosity, mutations and protein expression. Anticancer Res 2014;34:1387-1400.
Kim J, Coffey DM, Creighton CJ, et al. High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc Natl Acad Sci U S A 2012;109:3921-3926.
DeGraffenried LA, Fulcher L, Friedrichs WE, et al. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/ Akt pathway. Ann Oncol 2004;15:1510-1516.
Li YL, Tian Z, Wu DY, et al. Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions. World J Gastroenterol 2005;11:285-288.
Adamczyk A, Niemiec J, Janecka A, et al. Prognostic value of PIK3CA mutation status, PTEN and androgen receptor expression for metastasis-free survival in HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting. Pol J Pathol 2015;66:p. 133-141.
Chiang KC, Hsu SY, Lin SJ, et al. PTEN Insufficiency Increases Breast Cancer Cell Metastasis In Vitro and In Vivo in a Xenograft Zebrafish Model. Anticancer Res 2016;36:3997-4005.
Rimawi MF, De Angelis C, Contreras A, et al. Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat 2018;167:731-740.
Wu ZH, Tao ZH, Zhang J, et al. MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer. Tumour Biol 2016;37:7245-7254.
Apostolou P, Fostira F. Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int 2013;2013:747318.
García JM, Silva J, Peña C, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 2004;41:117-124.
Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37:828-830.
Starink TM, van der Veen JP, Arwert F, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986;29:222-233.
Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943-1947.
Eng C. Role of PTEN, a lipid phosphatase upstream effector of protein kinase B, in epithelial thyroid carcinogenesis. Ann N Y Acad Sci 2002;968:213-221.
Nelen MR, Padberg GW, Peeters EA, et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 1996;13:114-116.
Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 1997;57:2124-2129.
Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356-362.
Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997;16:64-67.
Marsh DJ, Dahia PL, Zheng Z, et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 1997;16:333-334.
Guanti G, Resta N, Simone C, et al. Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. Hum Mol Genet 2000;9:283-287.
Garcia JM, Silva JM, Dominguez G, et al. Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res Treat 1999;57:237-243.
Bose S, Crane A, Hibshoosh H, et al. Reduced expression of PTEN correlates with breast cancer progression. Hum Pathol 2002;33:405-409.
Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 1999;18:7034-7045.
Luo S, Chen J, Mo X. The association of PTEN hypermethylation and breast cancer: a meta-analysis. Onco Targets Ther 2016;9:5643-5650.
Salvesen HB, MacDonald N, Ryan A, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer 2001;91:22-26.
Kang YH, Lee HS, Kim WH. Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest 2002;82:285-291.
Soria JC, Lee HY, Lee JI, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 2002;8:1178-1184.
Siddiqui S, Akhter N, Deo SV, et al. A study on promoter methylation of PTEN in sporadic breast cancer patients from North India. Breast Cancer 2016;23:922-931.
Minami A, Nakanishi A, Ogura Y, et al. Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair. Front Oncol 2014;4:318.