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ICTMI 2017 pp 151-161 | Cite as

Significance of MTA1 Expression Status in Progesterone Responsiveness of Endometrial Cancer Cells

  • J. S. Chithra
  • S. Asha NairEmail author
Conference paper

Abstract

Progesterone or progestin therapy is given to endometrial cancer (EC) patients when surgery and chemotherapy are not acceptable treatment modalities due to various reasons. The success rate of this therapy is quite often low mainly because of resistance and non-responsiveness in patients. The presence of progesterone receptors (PR) is necessary for progesterone (P4)-induced transcription but not sufficient. Along with the ligand–receptor binding, recruitment of transcriptional co-regulators is essential for induction of transcription. In our study, we have investigated whether the level of transcriptional coregulator, metastasis tumor antigen 1 (MTA1) level influences progesterone-mediated transcriptional regulation and P4 responsiveness in EC cells. Ishikawa cells in which MTA1 is over-expressed or silenced are treated with progesterone, and the gene expression profile of relevant genes involved in invasion, EMT, and drug resistance are studied by real-time PCR. Cells with high expression of MTA1 showed a gene expression profile similar to EMT signature and enhanced drug transporter expression. Progesterone treatment is also found to differentially regulate progesterone receptor expression in MTA1 over-expressed and silenced cells. To understand the mechanism of differential gene regulation by progesterone in MTA1 high/low cells, further analysis is required. Along with the PR status, MTA1 level is highly significant in determining the outcome of progesterone treatment of endometrial cancer cells.

Keywords

Endometrial cancer Progesterone Invasion EMT E-cadherin Drug transporter Progesterone receptor 

Notes

Acknowledgements

Chithra J. S. was financially supported by Grant No. 09/716(0318)/2011-EMR-1 from CSIR, Government of India.

References

  1. 1.
    Lacey JV, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C (2005) Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Prev Biomarkers 14:1724–1731. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16030108. Accessed on 06 Oct 2017CrossRefGoogle Scholar
  2. 2.
    Chaudhry P, Asselin E (2009) Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr Relat Cancer 16:363–380. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19190080. Accessed on 23 July 2014CrossRefGoogle Scholar
  3. 3.
    Burke WM, Orr J, Leitao M, Salom E, Gehrig P, Olawaiye AB, Brewer M, Boruta D, Herzog TJ, Shahin FA (2014) SGO clinical practice endometrial cancer Working Group. Endometrial cancer: A review and current management strategies: part II. Gynecol oncol Aug 1, 134(2):393–402CrossRefGoogle Scholar
  4. 4.
    Dai D, Wolf DM, Litman ES, White MJ, Leslie KK (2002) Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. Cancer Res 62:881–886. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11830547
  5. 5.
    Smid-Koopman E, Blok LJ, Kühne LCM, Burger CW, Helmerhorst TJM, Brinkmann AO et al (2003) Distinct functional differences of human progesterone receptors A and B on gene expression and growth regulation in two endometrial carcinoma cell lines. J Soc Gynecol Invest 10:49–57. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12517594. Accessed on 18 Aug 2017
  6. 6.
    Toh Y, Pencil SD, Nicolson GL (1994) A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J Biol Chem 269:22958–22963. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8083195. Accessed on 18 Aug 2017
  7. 7.
    Yao Y-L, Yang W-M (2003) The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity. J Biol Chem 278:42560–42568. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12920132. Accessed on 17 Aug 2014CrossRefGoogle Scholar
  8. 8.
    Talukder AH, Mishra SK, Mandal M, Balasenthil S, Mehta S, Sahin AA, et al (2003) MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions. J Biol Chem 278:11676–11685. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12527756. Accessed on 17 Aug 2014CrossRefGoogle Scholar
  9. 9.
    Mishra SK, Yang Z, Mazumdar A, Talukder AH, Larose L, Kumar R (2004) Metastatic tumor antigen 1 short form (MTA1s) associates with casein kinase I-γ2, an estrogen-responsive kinase. Oncogene 23:4422–4429. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15077195. Accessed on 31 May 2017CrossRefGoogle Scholar
  10. 10.
    Balasenthil S, Broaddus RR, Kumar R (2006) Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol 37:656–661. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16733204. Accessed on 17 Aug 2014CrossRefGoogle Scholar
  11. 11.
    Balasenthil S, Broaddus RR, Kumar R (2006) Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Hum Pathol 37:656–661. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16733204. Accessed on 22 Aug 2016CrossRefGoogle Scholar
  12. 12.
    Kong X, Xu X, Yan Y, Guo F, Li J, Hu Y, et al (2014) Estrogen regulates the tumour suppressor MiRNA-30c and its target gene, MTA-1, in endometrial cancer. In: Campbell M (ed) PLoS One 9:e90810 Public Library of Science. Retrieved from http://dx.plos.org/10.1371/journal.pone.0090810. Accessed on 16 Aug 2017CrossRefGoogle Scholar
  13. 13.
    Yang CP, DePinho SG, Greenberger LM, Arceci RJ, Horwitz SB (1989) Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus. J Biol Chem 264:782–788. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2562956. Accessed on 18 Aug 2017
  14. 14.
    Uharcek P (2008) Prognostic factors in endometrial carcinoma. J Obstet Gynaecol Res 34:776–783. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18958927. Accessed on 6 Oct 2017CrossRefGoogle Scholar
  15. 15.
    Saunders WB (2006) High twist expression is involved in infiltrative endometrial cancer and affects patient survival. Hum Pathol 37:431–438. Retrieved from http://www.sciencedirect.com/science/article/pii/S0046817706000360. Accessed on 4 Oct 2017
  16. 16.
    Van Der Horst PH, Wang Y, Vandenput I, Kühne LC, Ewing PC, Van Ijcken WF, Van Der Zee M, Amant F, Burger CW, Blok LJ (2012) Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer. PLoS One Jan 25, 7(1):e30840Google Scholar
  17. 17.
    Bokhari AA, Lee LR, Raboteau D, Hamilton CA, Maxwell GL, Rodriguez GC et al (2014) Progesterone inhibits endometrial cancer invasiveness by inhibiting the TGF pathway. Cancer Prev Res 7:1045–1055. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25070663. 5 Oct 2017CrossRefGoogle Scholar
  18. 18.
    González-Rodilla I, Aller L, Llorca J, Muñoz A-B, Verna V, Estévez J, et al (2013) The E-cadherin expression versus tumor cell proliferation paradox in endometrial cancer. Anticancer Res 33:5091–5095. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24222154. Accessed on 5 Oct 2017
  19. 19.
    Athanassiadou P, Athanassiades P, Grapsa D, Gonidi M, Athanassiadou AM, Stamati PN et al (2007) The prognostic value of PTEN, p 53, and beta-catenin in endometrial carcinoma: a prospective immunocytochemical study. Int J Gynecol Cancer 17:697–704. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17504383. Accessed on 6 Oct 2017CrossRefGoogle Scholar
  20. 20.
    Evseenko DA, Paxton JW, Keelan JA (2007) Independent regulation of apical and basolateral drug transporter expression and function in placental trophoblasts by cytokines, steroids, and growth factors. Drug Metab Dispos 35:595–601. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17237156. Accessed on 6 Oct 2017CrossRefGoogle Scholar
  21. 21.
    Wang H, Zhou L, Gupta A, Vethanayagam RR, Zhang Y, Unadkat JD, et al (2006) Regulation of BCRP/ABCG2 expression by progesterone and 17beta-estradiol in human placental BeWo cells. AJP Endocrinol Metab 290:E798–E807. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16352672. Accessed on 6 Oct 2017CrossRefGoogle Scholar
  22. 22.
    Vore M, Leggas M (2008) Progesterone acts via progesterone receptors A and B to regulate breast cancer resistance protein expression. Mol Pharmacol 73:613–615. Retrieved from http://molpharm.aspetjournals.org/content/73/3/613.fullCrossRefGoogle Scholar
  23. 23.
    Vore M, Leggas M (2007) Progesterone acts via progesterone receptors A and B to regulate breast cancer resistance protein expression. Mol Pharmacol 73:613–615. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18086804CrossRefGoogle Scholar
  24. 24.
    Bouchard P (1999) Progesterone and the progesterone receptor. J Reprod Med 44:153–157. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11392025
  25. 25.
    Prange-Kiel J, Rune G, Zwirner M, Wallwiener D, Kiesel L (2001) Regulation of estrogen receptor α and progesterone receptor (isoform A and B) expression in cultured human endometrial cells. Exp Clin Endocrinol Diabetes 109:231–237. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11453036CrossRefGoogle Scholar
  26. 26.
    Jancis EM, Carbone R, Hochberg RB, Dannies PS (1993) Rapid stimulation of rhodamine 123 efflux from multidrug-resistant KB cells by progesterone. Biochem pharmacol. Nov 2, 46(9):1613–9CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Cancer Research Program-4Rajiv Gandhi Centre for BiotechnologyTrivandrumIndia

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