Abstract P5-14-06: Towards breast cancer prevention through reduced breast density: Suppressive effects of tamoxifen on normal breast epithelial cells

Abstract

Background: Breast density is positively associated with risk of breast cancer and the local microenvironment in the normal breast is known to significantly impact breast cancer initiation and further progression. The selective estrogen receptor modulator tamoxifen, with beneficial clinical effects on breast cancer recurrence, has also been shown to reduce mammographic density potentially explaining the primary preventive effects of tamoxifen. Still, important gaps persist regarding the cellular and molecular basis of how tamoxifen modifies breast density and subsequently breast cancer risk. Purpose: To investigate the impact by tamoxifen on normal human breast epithelial cells (MCF-10A) with the additional ambition to mimic variations in breast density on the cellular level. Experimental design: Effects of tamoxifen on MCF-10A cells at different cellular densities were evaluated in vitro. Flow cytometry and the sulforhodamine-B assay were used to assess cell cycle distribution and proliferation. Cell adhesion to extracellular matrix proteins was analyzed using hexosaminidase assay. Modulation of integrin receptor levels was determined by Western immunoblotting. Results: Tamoxifen exposure resulted in impaired cell cycle progression of human breast epithelial cells with a dose-dependent G2/M-phase arrest and reduced cell proliferation. Irrespective of tamoxifen treatment, the percent cellular adhesion to fibronectin and collagen type I by MCF-10A cells was significantly greater in high-density models compared to low-density models. Following tamoxifen treatment the adhesion was reduced in all density models. Consistent with the tamoxifen-induced lower adhesion, the integrin α1 and β3 levels were reduced in a dose-dependent way. Conclusion: These data support the hypothesis that tamoxifen affects the normal breast epithelium and its adhesion capacity, which may contribute to the clinically observed decrease in breast density and a potential reduced risk of breast tumor establishment. Citation Format: Rosendahl AH, Puig Blasco L, Borgquist S. Towards breast cancer prevention through reduced breast density: Suppressive effects of tamoxifen on normal breast epithelial cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-14-06.

Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells

“…Tamoxifen has been reported to have beneficial effects on normal breast tissue. Tamoxifen affects the normal breast epithelium and its adhesiveness, which probably contributes to the clinically observed decrease of breast density and thus could lead to a potentially reduced risk of developing breast tumors [ 29 ]. The research group around Daurio et al examined the action mechanism of tamoxifen on various breast cancer cell lines.…”