Authors: Stefano Rossetti, Francesca Corlazzoli, Alex Gregorski, Nurul Hidayah A. Azmi and Nicoletta Sacchi

Stefano Rossetti

Department of Cancer Genetics; Roswell Park Cancer Institute; Buffalo, NY USA
These authors contributed equally to this work.

Francesca Corlazzoli

Department of Cancer Genetics; Roswell Park Cancer Institute; Buffalo, NY USA
These authors contributed equally to this work.

Alex Gregorski

Department of Cancer Genetics; Roswell Park Cancer Institute; Buffalo, NY USA

Nurul Hidayah A. Azmi

Department of Cancer Genetics; Roswell Park Cancer Institute; Buffalo, NY USA

Nicoletta Sacchi

Corresponding author: nicoletta.sacchi@roswellpark.org
Department of Cancer Genetics; Roswell Park Cancer Institute; Buffalo, NY USA

Abstract:
Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process.

Received: July 31, 2012; Accepted: August 23, 2012; Published Online: August 30, 2012

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