Endogenous Circadian Clocks in Canine Mammary Tumor Cells Modulate Expression of Estrogen Receptor beta (ERβ)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-300
Shay Bracha1, Kelly Hughes1, Cheri Peyton Goodall2 and Patrick Everett Chappell*1
1Oregon State University College of Veterinary Medicine, Corvallis, OR, 2Oregon State University, College of Veterinary Medicine, Corvallis, OR
Several previous studies indicate that human breast cancer initiation and progression is initially estrogen-dependent, and that the relative abundance of estrogen receptor alpha (ERα) and ERβ is associated with tumor severity and metastatic potential. Other recent work suggests that endogenous circadian clock clock rhythms are often disrupted in breast and prostate cancer cell lines, in contrast with rhythms observed in normal epithelial cells. Since an interaction among clock transcription factors and ERs has been observed in breast cancer cells, we sought to determine what role the clock may play in the regulation of ER levels in these cancers, using cultured mammary tumor lines from canines, who often exhibit spontaneous mammary tumors that are heavily dependent on previous estrogen exposure in females that are not spayed until later in life.

Our results reveal the presence of circadian clock oscillations in our ER-positive tumor cells, a finding observed previously in human breast cancer cells. Circadian rhythms of ERα and ERβ expression were absent in these cells, however, suggesting that coupling of the clock mechanism to ER cycling is disrupted. Interestingly, treatment of canine tumor cells with sirtinol, an inhibitor of the histone deacetylase (HDAC) class III Sirt1, initiated circadian oscillations of ERβ (esr2) expression. Additionally, inhibition of class I HDACs with valproic acid resulted in a striking increase (but not rhythmicity) of ERβ, but not ERα, expression, demonstrating that chromatin remodeling mechanisms play a role in ER expression levels in mammary cancer. The observation of ERβ expression rhythms in the presence of Sirt1 inhibition suggests a clock control of ERβ abundance that may typically be disrupted in mammary cancer. A lack of proper temporal steroid hormone receptor-mediated activation and/or repression of multiple genes may represent one mechanism of tumor etiology or progression. Current studies are examining if resumption of ERβ rhythmicity via HDAC inhibition could result in alterations in proliferative rate of mammary tumors.

Nothing to Disclose: SB, KH, CPG, PEC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: College of Veterinary Medicine internal grant 2012 awarded to SB