Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Estrogen receptor integrative genomics and signalling networks in breast cancer and endocrine resistance (#98)

Benita S Katzenellenbogen 1 , Zeynep Madak-Erdogan 1 , Anna Bergamaschi 1 , Ping Gong 1 , John A Katzenellenbogen
  1. University of Illinois at Urbana-Champaign, Urbana, IL, United States

Understanding the factors and signaling networks that drive breast cancer proliferation, aggressiveness, and resistance to cancer therapies is of major importance in improving prevention and treatment of breast cancer. Estrogen receptor α (ERα) is a crucial regulator of the behavior of over 70% of human breast cancers. ERα controls numerous genes and signaling pathways, and ERβ is often co-present and working along with ERα in many breast tumors. We have been studying how diverse estrogens, working through ERs, regulate the phenotypic properties of breast cancer cells. We have also been interested in elucidating the changes that occur in these cells when they become resistant to endocrine or chemotherapies. Our studies have investigated the interrelationships of estrogen receptor alpha (ERα) with ER-beta and with coregulators. The studies have revealed critical associations with protein kinases and with actin-binding proteins that regulate the intracellular localization of key factors and the dynamics of chromatin binding and gene expression, resulting in alterations in cancer cell motility and invasiveness, and in proliferation and metabolic regulation. We have examined the activities of a variety of natural and synthetic ligands, including botanical estrogens consumed in the diet or in dietary supplements, and investigated how these receptor-coregulator-protein kinase-actin remodeling protein networks function to control breast cancer cell behavior and phenotypic properties. The transcription factor FoxM1 and the scaffold adaptor protein 14-3-3ζ, which are often overexpressed and amplified in breast cancer, are key players in bringing about alterations in gene expression and cell signaling that impact responsiveness or resistance to drug treatments in ER-positive and ER-negative breast cancers. We will discuss mechanisms by which these proteins engender resistance. Targeting these factors might improve clinical outcome and delay or prevent resistance to cancer treatments.

(Supported by grants from The Breast Cancer Research Foundation and the NIH)