Estrogen receptor α (ERα) upregulation causes abnormal cell proliferation in about two thirds of breast cancers, yet understanding of the underlying mechanisms remains incomplete. Here, we show that high expression of the microRNA miR-375 in ERα-positive breast cell lines is a key driver of their proliferation. miR-375 overexpression was caused by loss of epigenetic marks including H3K9me2 and local DNA hypomethylation, dissociation of the transcriptional repressor CTCF from the miR-375 promoter, and interactions of ERα with regulatory regions of miR-375. Inhibiting miR-375 in ERα-positive MCF-7 cells resulted in reduced ERα activation and cell proliferation. A combination of expression profiling from tumor samples and miRNA target prediction identified RASD1 as a potential miR-375 target. Mechanistic investigations revealed that miR-375 regulates RASD1 by targeting the 3′ untranslated region in RASD1 mRNA. Additionally, we found that RASD1 negatively regulates ERα expression. Our findings define a forward feedback pathway in control of ERα expression, highlighting new strategies to treat ERα-positive invasive breast tumors. Cancer Res; 70(22); 9175-84. ©2010 AACR.

BackgroundThere is disagreement among studies of health-related quality of life (HRQoL) changes in breast cancer patients over time. Reportedly, assessment of HRQoL prior to diagnosis may be crucial to provide a clear point of comparison for later measurements. The aims of this study were (1) to investigate changes in HRQoL, sense of coherence (SOC), spirituality and religious coping in a group of women with breast cancer from the pre-diagnosis phase to 6 months later in comparison with a control group, and (2) to explore the predictor role of SOC, spirituality, and religious coping within the breast cancer group at the 6-month follow-up.MethodsA sample of women with breast cancer (n = 162) and a matched control group (n = 210) responded to the following instruments on both occasions: the European Organization for Research and Treatment of Cancer QLQ-C30, the SOC Scale, the Spiritual Perspective Scale and the Brief Religious Coping Scale. A series of General Linear Model (GLM) Repeated Measures was used to determine changes between the groups over time. Also, Multiple Linear Regression analyses were applied to each of the HRQoL dimensions, as dependent variable at the 6 months follow-up.ResultsPhysical and role function, fatigue, and financial difficulties were rated worse by the women with breast cancer during the first 6 months in comparison to the controls, which was both a statistically (p < 0.001) and clinically significant difference. Women had better scores for global quality of life (p < 0.001), and emotional functioning (p < 0.01) during the same period of time. The degree of SOC (p < 0.01) and baseline ratings of several dimensions of HRQoL (p < 0.05) were the most important predictors of HRQoL changes.ConclusionsCollecting HRQoL data before a final diagnosis of breast cancer is important to identify women at risk of deterioration in HRQoL during and after treatment. Special attention should be paid to physical and role functioning impairment, fatigue, and financial difficulties experienced by these women. These results underscore that the degree of SOC may be more important as a predictor for HRQoL changes in this sample than spirituality and religious coping.