Abstract 2111: Role of gene repression by estrogen in invasiveness of breast cancer cells

Abstract

Abstract More than 75% of breast tumors are estrogen receptor (ER)-positive and require estrogen for their growth and survival. Long-term adjuvant therapies that disrupt estrogen signaling, in particular tamoxifen and aromatase inhibitors, are a mainstay in breast cancer treatment. The principal focus of mechanistic studies evaluating the role of estrogen in breast cancer proliferation has been on gene activation by estrogen and its antagonism by anti-estrogens. Gene repression by estrogen and its antagonism by anti-estrogens have unclear physiological and therapeutic consequence in breast cancer. In this study, we found that estrogen-repressed genes but not estrogen-activated genes overlapped the gene overexpression signature of clinical progression of ductal carcinoma in situ to invasive ductal carcinoma. An extensive gene ontology analysis revealed that genes repressed by estrogen are enriched for functions known to collectively support breast cancer progression. In ER-positive breast cancer cells tamoxifen prevented gene repression by estrogen. In these cells, estrogen inhibited invasiveness in a manner that was opposed by tamoxifen. These effects of estrogen and tamoxifen on gene repression and invasiveness also occurred in Her2+/ER+ cells whose growth was hormone-independent and insensitive to tamoxifen. The effects were also independent of ErbB2 gene regulation by estrogen. Several ER co-repressors supported repression of the tumor progression genes by estrogen. Gene repression by estrogen was causally linked to inhibition of invasiveness as a co-repressor binding site mutation in ER that selectively disrupted the ability of estrogen to repress genes also prevented inhibition of invasiveness. Gene repression by estrogen involved ER binding at non-classical chromatin sites that was prevented by tamoxifen. The findings offer a mechanistic understanding of the invasive potential of ER+ breast cancer cells that have evaded growth inhibition during conventional anti-estrogen treatments. Citation Format: Mugdha Patki, Marcela d'Alincourt Salazar, Robert Trumbly, Manohar Ratnam. Role of gene repression by estrogen in invasiveness of breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2111. doi:10.1158/1538-7445.AM2014-2111