Abstract 5240: Breast cancer in the metastatic niche: A role for stress-induced dormancy

Abstract

Abstract Breast cancer dormancy in the metastatic site allows tumors to avoid clinical detection and evade treatment leading to recurrence after years or decades, with devastating mortality rates. How the aggressive carcinoma cells that initially underwent a cancer-associated Epithelial to Mesenchymal Transition (EMT) from the primary tumor to disseminate and maintain a long-term dormant state in an ectopic site is unknown. We have found that normal parenchymal cells of certain metastatic organs cause a partial reversion of the EMT to a more epithelial phenotype (Mesenchymal to Epithelial Reversion Transition, or MErT). Compared to carcinoma cells in the primary breast tumor, MErT is characterized by increased E-cadherin expression, MAPK and AKT signaling, and chemoresistance. While this phenotype should reflect low proliferation or quiescence, the MErT cells in vitro have heretofore maintained a highly proliferative state. Herein we demonstrate that a pre-stressed hepatic microenvironment allows for EMT cells to increase their MErT phenotype and to become dormant. Our research strategy is to modulate the initial liver stress through biochemical challenges applied to primary rat hepatocytes co-cultured with hepatic resident cells and a human immortalized breast cancer cell line (MDA-MB-231). Biochemical challenges (e.g. TGFβ, TNFα, IL-6, EGF, HGF, and DAMPS) are applied in varying concentrations and incubation periods in order to pre-stress the hepatic culture. In order to maintain hepatic metabolic function we implement a novel 3D perfused micro-well bioreactor. As a secondary aim we explore whether E-cadherin expression is required for metastatic seeding through splenetic injections in immune compromised mice. We aim to uncover novel targets that are not strictly against the cancer cells, but rather, against shared molecular pathways across cancer, parenchymal, and non-parenchymal cells within the hepatic niche. Sustaining and perhaps enhancing the ectopic site resilience may yield therapies directed toward maintaining dormant carcinomas so that secondary EMTs will be blocked and cancer recurrence greatly reduced. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5240. doi:1538-7445.AM2012-5240