PT - JOURNAL ARTICLE AU - Kennedy, Catherine AU - Byth, Karen AU - Clarke, Christine L. AU - deFazio, Anna TI - Cell Proliferation in the Normal Mouse Mammary Gland and Inhibition by Phenylbutyrate 1 This work was supported by the National Breast Cancer Foundation, the New South Wales Cancer Council, and the Australian Cancer Foundation. <a id="xref-fn-1-1" class="xref-" href="#fn-1"><sup>1</sup></a> DP - 2002 Oct 01 TA - Molecular Cancer Therapeutics PG - 1025--1033 VI - 1 IP - 12 4099 - http://mct.aacrjournals.org/content/1/12/1025.short 4100 - http://mct.aacrjournals.org/content/1/12/1025.full SO - Mol Cancer Ther2002 Oct 01; 1 AB - Ovarian hormones have a pivotal role in the control of proliferation in the mammary gland, and cumulative life-time exposure to ovarian hormones is known to be a determinant of breast cancer risk. We have shown previously that a p.o.-active, long-acting butyrate analogue, sodium phenylbutyrate (PB), reduced proliferation in normal and malignant human breast cells in culture and reduced expression of ovarian hormone receptors, suggesting that PB had cellular effects consistent with decreasing breast cancer risk. The aim of this study was to determine the in vivo effects of PB in the normal mammary gland on epithelial cell proliferation, estrogen receptor α (ERα) expression, and cyclin D1 expression. BALB/c mice were treated with PB, delivered by mini-osmotic pumps, for 7 days. Moderate (250 mg/kg/day) and high (500 mg/kg/day) PB treatment resulted in a decrease in proliferation in mammary epithelial cells (P &lt; 0.001), determined by bromodeoxyuridine incorporation. Analysis of ERα immunostaining revealed a significant reduction in moderate- and high-treatment groups (P = 0.01 and P=0.02), and expression of cyclin D1 was virtually ablated (P &lt; 0.001). Histone deacetylase inhibition is a known mechanism of butyrate action, and consistent with this, PB increased levels of acetylated histone H3 in the mammary gland. In summary, PB decreased proliferation in the mammary gland in vivo at clinically achievable doses. Decreased proliferation was accompanied by changes in the levels of ERα and cyclin D1. These data show that PB modulates parameters thought to be involved in the carcinogenic process in the normal mammary gland, and compounds in this class may therefore be useful candidates for breast cancer chemoprevention.