Abstract P4-03-11: Fibroblasts isolated from the “normal-like” tissue adjacent to breast tumours suppress healthy epithelial progenitor cell proliferation while supporting tumour cell growth

Abstract

Abstract The tissue adjacent to breast tumors has been referred to as “normal-like” tissue despite exhibiting many alterations at epigenetic and gene expression levels consistent with enhanced proliferation and wound healing signatures. However, the influence of such alterations on the proliferation and differentiation of healthy breast progenitors is currently unknown. Fibroblasts are a major component of microenvironment for the healthy and malignant breast cells. We therefore, isolate fibroblast from primary breast tumors, tissue adjacent to tumors (TAT) and the healthy breast tissue and examine their ability to support proliferation of healthy and malignant breast cells. To characterize the TAT samples we first utilized clonal co-culture assays using breast cells obtained from the healthy breast tissue (reduction mammoplasty sample, RM) and the healthy fibroblasts. Our results suggested that the TAT samples surprisingly contained significantly decreased pool of progenitors compared to the RM samples. In order to study the underlying mechanism, we characterized fibroblasts derived from either the breast tumours (TAFs) or the TAT samples (TATF) or the RM normal samples (NAFs) and assessed their role on breast progenitor cell functions. Fibroblasts were isolated from the ER+ and ER- breast tumours and their adjacent breast tissue. We observed that matrigel co-cultures consisting of RM samples and NAFs led to a 5.5-fold expansion of the progenitors, whereas the co-cultures of TAT or the RM samples with either TAFs or TATFs failed to show expansion of epithelial progenitors. The comparative secretome analysis of the NAFs and the TATFs identified TGFβ as a candidate molecule primarily secreted only by the TATFs and not by NAFs. Interestingly, blocking TGFβ signaling restored both TAFs' and TATFs' ability to support the expansion of healthy progenitors in matrigel cultures. Lastly, we found that TAFs were able to enhanced breast cancer cell proliferation in vivo and in vitro but to a lesser extent than the TAFs. Our observations suggest that the tissues adjacent to breast tumours are transformed into a TGFβ-enriched environment that is supportive of breast tumour growth while suppressing the proliferation and differentiation potentials of the healthy breast progenitors. Our data also suggest that the use of TGFβ blockers may be important in reducing risk of local breast tumour recurrence. Citation Format: Chatterjee S, Berdnikov A, Lee-Wing V, Safneck J, Buchel E, Raouf A. Fibroblasts isolated from the “normal-like” tissue adjacent to breast tumours suppress healthy epithelial progenitor cell proliferation while supporting tumour cell growth [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-03-11.