EZH2 Is a Key Player in Progestin-Induced Breast Cancer Growth and Tamoxifen Resistance - See more at: http://press.endocrine.org/doi/book/10.1210/endo-meetings.2016.TB.2#sthash.4tcwo5lm.dpuf

CENCIARINI, MAURO; GÓMEZ POVIÑA, JUAN CRUZ; MERCOGLIANO, MARÍA FLORENCIA; DI GIORGIO, NOELIA; SCHILLACI, ROXANA; ELIZALDE, PATRICIA V.; IZZO, FRANCO; PROIETTI, CECILIA J.

Boston

Congreso; Endocrine Society´s 98th Annual Meeting and Expo; 2016

Endocrine Society

More than 70% of breast cancers (BC) express estrogen and progesterone receptors (ER and PR, respectively), and patients positive for ER expression are treated with tamoxifen (TAM) as endocrine therapy. Nevertheless, more than one third of patients are not responsive to therapy. Even though PR involvement in BC progression has been well acknowledged, the molecular mechanisms involved remain unclear. We have recently described that the synthetic progestin medroxiprogesterone acetate (MPA) induced the interaction between PR and the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3), an epigenetic mark associated with transcriptional repression. This results in the downregulation of tumor suppressor GATA3 and the increase in cell proliferation of the human breast cancer cell line T47D (1). Since EZH2 has been implicated in the progression of several types of cancer, including those of the breast, and our own previous results indicate a functional relationship between PR and EZH2 in BC cells, we hypothesized that EZH2 could function as a mediator in the pro-tumorigenic effects of progestins, targeting specific tumor suppressor and differentiating genes to allow ER/PR-positive BC growth. We inoculated a progesterone pellet in ovariectomized BALB/c mice and observed an increase in EZH2 expression, in H3K27me3 global levels, and in the proliferation marker Ki67, and a decrease in GATA3 mRNA levels in the mammary gland. In addition, we found that EZH2 expression is higher in the progestin-induced C4HD murine breast tumor than in the normal mammary gland. A meta-analysis of available datasets of breast cancer patients using the software Oncomine showed that EZH2 is overexpressed in human ductal breast cancer when compared to normal tissue. In order to assess the importance of EZH2 in breast cancer growth, we transfected T47D cells with EZH2 siRNAs and found that MPA-induced in vitro cell proliferation and GATA3 transcriptional repression were prevented. These results confirm EZH2 requirement for progestin-induced proliferative effects. On the other hand, we found that MPA-pretreatment induced TAM resistance in TAM-sensible T47D cells, and that EZH2 silencing averted this resistance switch, suggesting a link between TAM resistance and PR activation through EZH2-mediated epigenetic reprogramming. Furthermore, by performing in silico analysis through the publicly available software KM-plotter, we found that increased EZH2 expression in ER/PR-positive BC patients correlates with reduced response to endocrine therapy. Taken together, these results show a key role of EZH2 in progestin-induced breast cancer and provide a novel therapeutic target for TAM-resistant breast cancer. - See more at: http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2016.TB.2.OR23-5#sthash.8IskVzsY.dpuf