Abstract 3845: The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction: Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from pre-menopausal African-American (AA) or Caucasian-American (CA) breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo. We chose these two populations because of the well-documented predisposition of AA to develop aggressive, highly metastatic breast cancer compared to CA women. Methods: The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast-ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested in vitro via soft agar and invasion assays, and in vivo via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry. Results: Mouse mammary glands humanized with pre-menopausal CA-fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA-humanized glands. Examination of 164 extracellular matrix (ECM) molecules and cytokines from CA-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast-ECM was isolated; invasion and soft agar assays demonstrated that ER-/PR- cells were significantly more aggressive when in contact with AA ECM, as were ER+/PR+ cells with CA ECM. Using zymography, protease activity was comparatively upregulated in CA ECM. In xenograft models, CA ECM significantly increased the tumorigenicity of ER+/PR+ cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed only 1,759 of ∼8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CA-unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically-active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CA breast tissue. Conclusions: This study details normal pre-menopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3845.