Abstract 3568: Induction of aberrant breast acinar morphogenesis by deregulation of an estrogen receptor alpha circadian circuit.

Abstract

Altered estrogen receptor alpha (ERA) signaling and altered circadian rhythms are both features of breast cancer. ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells (Rossetti et al., 2012a). Interestingly, we identified a circuit consisting of ERA and an estrogen-regulated loop consisting of PER2 and BMAL1, two circadian clock genes, in entrained ERA-positive breast epithelial cells. This estrogen-regulated circuit is apparently necessary for breast epithelial acinar morphogenesis, and its disruption by ERA knock down negatively affects both the estrogen-sustained circadian PER2-BMAL1mechanism and the formation of acini in three-dimensional (3D) culture on basement membrane. Conversely, knock down of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects both ERA circadian oscillations and 3D breast acinar morphogenesis (Rossetti et al., 2012b). This is the first evidence that a circuit comprising ERA and key circadian clock components is implicated in the acinar developmental processes of breast epithelial cells. Acknowledgments: this work was supported by the Department of Defense (DOD) Concept Award W81XWH0610657 (NS), the Breast Cancer Coalition of Rochester (NS), and the Friends for an Earlier Test for Breast Cancer Foundation (NS). Rossetti, S, Esposito, J, Corlazzoli, F, Gregorski, A, and Sacchi, N. (2012a). Entrainment of breast (cancer) epithelial cells detects distinct circadian oscillation patterns for clock and hormone receptor genes. Cell Cycle 11, 350-360. Rossetti, S, Corlazzoli, F, Gregorski, A, Azmi, NH, and Sacchi, N. (2012b). Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis. Cell Cycle 11, 3691-3700. Citation Format: Stefano Rossetti, Francesca Corlazzoli, Alex Gregorski, Nicoletta Sacchi. Induction of aberrant breast acinar morphogenesis by deregulation of an estrogen receptor alpha circadian circuit. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3568. doi:10.1158/1538-7445.AM2013-3568