Targeting EZH2 in progesterone receptor-positive breast cancer

YANMING WU; FELIPE GUSTAVO GERCOVICH; ROXANA SCHILLACI; MARA DE MARTINO; PATRICIA VIRGINA ELIZALDE; MARIA FLORENCIA CHERVO; SANDRA ARES; KEXIN XU; MAURO EZEQUIEL CENCIARINI; MATIAS AMASINO; ERNESTO GIL DEZA; FRANCO IZZO; CECILIA J PROIETTI

San Pablo

Conferencia; Second AACR International Conference Translational Cancer Medicine; 2018

On the basis of Estrogen Receptor (ER) presence, breast cancer (BC) patients are treated with selective ER modulators (SERMs), such as tamoxifen (TAM). However, approximately 40% of women receiving TAM experience tumor relapse. Even though Progesterone Receptor (PR) involvement in BC progression has been well acknowledged by us and others, the molecular mechanisms involved remain unclear. We have recently described that the synthetic progestin medroxiprogesterone acetate (MPA) induced the recruitment of PR and the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2) to tumor suppressor GATA3 promoter. EZH2 catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3), an epigenetic mark associated with transcriptional repression. This results in the down-regulation of tumor suppressor GATA3 and the increase in cell proliferation and tumor growth. EZH2 is often overexpressed in different types of cancers and associated with poor overall survival. We therefore hypothesized that EZH2 could function as a mediator of the pro-tumorigenic effects of progestins, targeting specific tumor suppressors and differentiating genes to allow ER/PR-positive BC growth. The objective of this work was to study the role of EZH2 in progestin-induced BC growth. In vitro studies were carriedout in the T47D human BC cell line and in primary cultures of the MPA dependent C4HD murine breast tumor. Firstly, MPA (10 nM) induced EZH2 expression after 18 and 24 h of treatment, seen by increased levels of both mRNA (qPCR, p