P1-03-04: In-Vitro Characterization of a Breast Cancer Microenvironment with Epithelial-to-Mesenchymal Transition (EMT) Characteristics.

Abstract

Abstract Non-neoplastic tissues adjacent to tumor is known to influence the progression of the disease. We and others found that there are two types of microenvironment, one of these highly expresses genes associated with epithelial-to-mesenchymal transition (EMT). Tumor adjacent microenvironment (TAME) with wound responses have been observed in >90% of tumor-adjacent tissues, but EMT- characteristics seems to be less common and are observed in less than half of all patients. Our data suggest that the patients with EMT-TAME have worse breast cancer outcome, particularly among estrogen receptor positive patients. Thus, understanding the molecular cross talk between tumor cells and adjacent cells located in the TAME with EMT properties may identify targetable pathways that play a important role in breast cancer progression. Toward this end, we developed an in-vitro model system that can be used to probe paracrine signaling between cancer cells and adjacent cells undergoing EMT. We hypothesized that the presence of EMT signals in the TAME will alter the gene expression and phenotype of epithelial cells. We further hypothesized that the interactions between cancer cells and their TAME would be subtype dependent. Using cell line models of luminal and basal-like breast cancer, we performed cocultures with cancer cells and cell line models of EMT. The latter cell lines were HMLE cells transduced with either Snail or Twist, representing an intermediate state between an epithelial and a fully mesenchymal phenotype. This coculture system allows the study of heterotypic interactions between cancers and TAME cells with EMT characteristics. Gene expression, proliferation, migration, anchorage independent growth and cytokine production of different breast cancer and non-neoplastic cell lines were evaluated. We observed that coculture with models of EMT microenvironments altered the behavior of epithelial cells and that the gene expression changes were relevant to in-vivo in public datasets, showing correlations with both subtype and outcome. Cocultured cells acquired more migratory behavior and reduced expression of cellular adhesion genes, while simultaneously increasing anchorage independent growth and production of cytokines such as IL-6 and IL-8. Furthermore, we observed different response by luminal and basal-like breast cancer cells to the coculture condition, suggesting that the tumor-TAME interactions occur in a tumor subtype dependent fashion. These results reiterate the importance of the surrounding environment on cancer cell phenotypes and document that paracrine interactions with cells undergoing EMT may increase the aggressiveness of some cancers. Identification of specific signaling pathways that define interactions between specific breast cancer subtypes and their microenvironments will lead to new insights regarding tumor biology and identify potential pathway-specific biomarkers and/or targets for prognosis and treatment of breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-03-04.