Abstract 1102: miRNAs are key mediators of crosstalk between estrogen and progesterone regulating breast cancer invasiveness

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.1102-1102
• Main Author: McFall, Thomas B.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-1102

Even though estrogen receptor (ER)-positive breast tumors are exquisitely sensitive to anti-estrogen therapy, the disease is virtually incurable when it has progressed to ER+ distal metastasis. Therefore a better understanding of regulatory processes in ER+ breast tumor invasiveness is important. Invasive ER+ breast tumors frequently express high levels of the progesterone receptor (PR) isoform A (PR-A), relative to PR-B. We have previously reported that E2 strongly represses in vitro invasiveness below concentrations of E2 corresponding to median plasma and breast tissue levels post-menopause. Progesterone, at concentrations corresponding to postmenopausal levels, completely abrogates inhibition of invasiveness by E2. The ability of progestins to rescue invasiveness from estrogen regulation is exclusively mediated by PR-A. In contrast, at the high concentrations associated with luteal phase and pregnancy levels, progesterone induces invasiveness independent of E2 through PR-B. Interventions that target PR-A are limited by the fact that functional PR-A is needed to protect against E2-induced uterine dysplasia and hyperplasia. In order to attenuate PR-A dependent invasiveness, it is necessary to identify and target mediators of specific cross-talk between E2/ER and progestin/PR-A in the context of hormonal regulation of invasiveness. As micro-RNAs (miRs) are known to play a major role in the actions of E2, we investigated two possible modalities for miRs to mediate this cross talk: (1) Progesterone/PR-A could induce expression of critical miRs that attenuate suppressive effects of E2 on invasiveness; (2) E2-regulated miRs that directly influence invasiveness may be counter-regulated by progesterone/PR-A. Using microarray analysis and quantitative PCR in several ER+ cell lines, we identified five miRs (miR-6805, miR-584, miR-1228, miR-501, and miR-668) that were activated by progestin exclusively by PR-A, but were not regulated by E2. Whereas these miRs could serve as a signature of hyperactive PR-A, loss-of-function studies using miR inhibitors indicated that they did not play a functional role in the ability of PR-A to regulate invasiveness. An additional ten miRs were regulated by E2/ER (activated or repressed), in a manner that was counter-regulated by progestin/PR-A. Two of these miRs (miR-92a, and miR-26b) were identified using miR inhibitors to have a direct role in mediating the ability of progesterone to rescue invasiveness from E2 regulation. In co