The Iranian Journal of Obstetrics, Gynecology and Infertility

The Iranian Journal of Obstetrics, Gynecology and Infertility

PTEN Gene Expression and Tamoxifen-Resistance in Steroid Hormone Receptor Positive Breast Cancer Patients, a cross-sectional study between 2006 and 2016

Document Type : Original Article

Authors
Fereshteh Mohammadi Daloyi 1
Noorieh Sharifi 2
Fatemeh Homaei Shandiz 3
Lida Jarahi 4
1 Resident, Department of Clinic, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
2 Professor, Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
3 Associate Professor, Department of Radiotherapy and Oncology, Cancer Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
4 Associate Professor, Department of Community Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
10.22038/ijogi.2020.15959
Abstract
Introduction: PI3K/Akt/mTOR pathway is important in inducing resistance to hormone therapy in patients with hormone positive breast cancer. One regulator of this pathway is the PTEN gene. This study was performed with aim to compare the expression of PTEN gene in hormone receptor positive breast cancer patients between patients with sensitive and resistant to tamoxifen.
Methods: This cross-sectional and retrospective study was performed on 80 hormone receptor positive breast cancer patients who had referred to oncology clinics of Mashhad University of Medical Sciences from 2006 to 2016. Tissue samples of tamoxifen-sensitive and -resistant patients (recurrence/metastasis occurring during the first 5 years of adjuvant hormone therapy) were immunohistochemically evaluated for PTEN expression. Data were analyzed by SPSS software (version 16) and Independent t-test, U Mann-Whitney and chi-square tests. P<0.05 was considered statistically significant.
Results: In this study, 80 patients were evaluated in two groups of tamoxifen sensitive and resistant. The expression of PTEN in tamoxifen-sensitive and resistant patients was 97.5% and 27.5%, respectively (p=0.001). However, in patients with more advanced lymph node involvement, the expression of PTEN was significantly reduced (p=0.001), there was no significant relationship between PTEN expression and tumor size (p=0.19), tumor grade (p=0.14) and Her2/neu expression (p=0.85).
Conclusion: There is association between PTEN gene expression and tamoxifen resistance.
Keywords
Breast Cancer
Steroid Hormone Receptor Positive
Tamoxifen
Hormone Therapy Resistance
PTEN
  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6):394-424.
  2. Farhood B, Geraily G, Alizadeh A. Incidence and Mortality of Various Cancers in Iran and Compare to Other Countries: A Review Article. Iran J Public Health 2018; 47(3):309-316.
  3. Ito Y, Miyashiro I, Ito H, Hosono S, Chihara D, Nakata-Yamada K, et al. Long-term survival and conditional survival of cancer patients in Japan using population-based cancer registry data. Cancer Sci 2014; 105(11):1480-6.
  4. Nafissi N, Khayamzadeh M, Zeinali Z, Pazooki D, Hosseini M, Akbari ME. Epidemiology and Histopathology of Breast Cancer in Iran versus Other Middle Eastern Countries. Middle East Journal of Cancer 2018; 9(3):243-51.
  5. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98(19):10869-74.
  6. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 2015; 26(8):1533-46.
  7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015; 386(10001):1341-52.
  8. Wilson S, Chia SK. Treatment algorithms for hormone receptor-positive advanced breast cancer: applying the results from recent clinical trials into daily practice-insights, limitations, and moving forward. Am Soc Clin Oncol Educ Book 2013.
  9. Johnston SR. Acquired tamoxifen resistance in human breast cancer--potential mechanisms and clinical implications. Anticancer Drugs 1997; 8(10):911-30.
  10. Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem 1999; 263(3):605-11.
  11. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 1999; 96(8):4240-5.
  12. Mutter GL. Pten, a protean tumor suppressor. Am J Pathol 2001; 158(6):1895-8.
  13. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 1998; 95(23):13513-8.
  14. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95(1):29-39.
  15. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999; 13(22):2905-27.
  16. Shoman N, Klassen S, McFadden A, Bickis MG, Torlakovic E, Chibbar R. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod Pathol 2005; 18(2):250-9.
  17. Javadinia SA, Shahidsales S, Fanipakdel A, Mostafapour A, Joudi-Mashhad M, Ferns GA, et al. The Esophageal Cancer and the PI3K/AKT/mTOR Signaling Regulatory microRNAs: a Novel Marker for Prognosis, and a Possible Target for Immunotherapy. Curr Pharm Des 2018; 24(39):4646-51.
  18. Javadinia SA, Shahidsales S, Fanipakdel A, Joudi-Mashhad M, Mehramiz M, Talebian S, et al. Therapeutic potential of targeting the Wnt/beta-catenin pathway in the treatment of pancreatic cancer. J Cell Biochem 2018.
  19. Tanic N, Milovanovic Z, Tanic N, Dzodic R, Juranic Z, Susnjar S, et al. The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients. Cancer Biol Ther 2012; 13(12):1165-74.
  20. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol 2019; 30(8):1194-1220.
  21. Lindberg K, Helguero LA, Omoto Y, Gustafsson JA, Haldosen LA. Estrogen receptor beta represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: implications for tamoxifen sensitivity. Breast Cancer Res 2011; 13(2):R43.
  22. 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(7):672-6.
  23. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 2005; 65(7):2554-9.
  24. Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, et al. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer 2004; 112(3):407-10.
  25. Piekarski JH, Biernat W. Clinical significance of CK5/6 and PTEN protein expression in patients with bilateral breast carcinoma. Histopathology 2006; 49(3):248-55.
  26. Wang LL, Hao S, Zhang S, Guo LJ, Hu CY, Zhang G, et al. PTEN/PI3K/AKT protein expression is related to clinicopathological features and prognosis in breast cancer with axillary lymph node metastases. Hum Pathol 2017; 61:49-57.
  27. Bose S, Chandran S, Mirocha JM, Bose N. The Akt pathway in human breast cancer: a tissue-array-based analysis. Mod Pathol 2006; 19(2):238-45.
  28. Panigrahi AR, Pinder SE, Chan SY, Paish EC, Robertson JF, Ellis IO. The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. J Pathol 2004; 204(1):93-100.
  29. Milovanovic Z, Dzodic R, Susnjar S, Plesinac-Karapandzic V, Juranic Z, Tatic S. PTEN protein expression in postmenopausal steroid receptor positive early breast cancer patients treated with adjuvant tamoxifen. J BUON 2011; 16(1):46-51.
  30. Drury SC, Detre S, Leary A, Salter J, Reis-Filho J, Barbashina V, et al. Changes in breast cancer biomarkers in the IGF1R/PI3K pathway in recurrent breast cancer after tamoxifen treatment. Endocr Relat Cancer 2011; 18(5):565-77.
  31. Miller TW, Pérez-Torres M, Narasanna A, Guix M, Stål O, Pérez-Tenorio G, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 2009; 69(10):4192-201.
  32. Tokunaga E, Kimura Y, Mashino K, Oki E, Kataoka A, Ohno S, et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006; 13(2):137-44.
  33. Papa A, Pandolfi PP. The PTEN–PI3K Axis in Cancer. Biomolecules 2019; 9(4):153.
  34. Manning BD, Toker A. AKT/PKB Signaling: Navigating the Network. Cell 2017; 169(3):381-405.
  35. Bostner J, Karlsson E, Pandiyan MJ, Westman H, Skoog L, Fornander T, et al. Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Res Treat 2013; 137(2):397-406.
  36. deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 2004; 10(23):8059-67.
  37. Li Z, Yu D, Li H, Lv Y, Li S. Long noncoding RNA UCA1 confers tamoxifen resistance in breast cancer endocrinotherapy through regulation of the EZH2/p21 axis and the PI3K/AKT signaling pathway. Int J Oncol 2019; 54(3):1033-42.
The Iranian Journal of Obstetrics, Gynecology and Infertility
Volume 23, Issue 2
April 2020
Pages 9-19