miR-129-2 mediates down-regulation of progesterone receptor in response to progesterone in breast cancer cells

ABSTRACT

Objective: Hormonal therapy is an important component of first line of treatment for breast cancer. Response to hormonal therapy is influenced by the progesterone receptor (PR)-status of breast cancer patients. However as an early effect, exposure to progesterone decreases expression of PR in breast cancer cells. An understanding of the mechanism underlying down-regulation of PR could help improve response to hormonal therapy. Methods: We performed small RNA sequencing of breast cancer cells for identification of microRNAs targeting PR in response to progesterone treatment. Biochemical approaches were used to validate the findings in breast cancer cells. Results: Analysis of small RNA sequencing of four breast cancer cell lines treated with progesterone revealed an up-regulation of miR-129-2 independent of the PR status of the cells. We show that miR-129-2 targets 3′UTR of PR to down-regulate its expression. Furthermore, inhibition of miR-129-2 expression rescues the down-regulation of PR in breast cancer cells. Also, the expression levels of miR-129-2 was observed to be elevated in patients with low expression of PR in the TCGA cohort (n = 359). Conclusion: miR-129-2 mediates down-regulation of PR in breast cancer cells in response to progesterone, while anti-miR-129-2 could potentiate PR expression levels among patients with inadequate PR levels. Thus, modulation of activity of miR-129-2 could stabilize PR expression and potentially improve response to hormonal therapy under adjuvant or neo-adjuvant settings.

KEYWORDS:

• Breast cancer
• hormonal therapy
• progesterone
• progesterone receptor
• microRNA
• cancer genomics
• small RNA sequencing

Disclosure of potential conflict of interest

No potential conflict of interest was reported by the authors.

Acknowledgments

All members of the Dutt laboratory for critically reviewing the manuscript and Pawan Upadhyay for STR profiling of breast cancer cells. Small RNA sequencing were performed at Genotypic Pvt Ltd, Bangalore, India.

Authors' contributions

M.G. and A.D designed the research; M.G., P.C., N.G., H.D., K.P. and N.Y. performed the research; M.G., P.C. and A.D. analyzed the data; M.G., S.G., R.B. and A.D. wrote the paper. All the authors have read and approved the manuscript.

Funding

A.D. is supported by an Intermediate Fellowship from the Wellcome Trust/DBT India Alliance (IA/I/11/2500278), intramural grants [IRB project 2712], and by a grant from DBT (BT/MED/30/VNCI-Hr-RCA/2015). M.G., P.C., N.G. and N.Y. are supported by research fellowship from Homi Bhabha National Institute (HBNI), ACTREC-TMC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.