Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptor-alpha expression in human breast cancer.

The oestrogen receptor-alpha (ER alpha) differs in expression and regulation in breast cancer and, by studying the co-factor cyclin D1 as well as changes in the microenvironment, we here delineate two conditions that potentially cause regional down-regulation of the receptor. Heterogeneously expressed ER alpha was observed in 24 out of 134 of the studied breast cancer samples. In 6 out of 24 of the heterogeneous tumours, there was a clear inverse association between cyclin D1 protein/gene amplification and presence of ER alpha. In a subset of 120 tumours, analysed by Western blotting and ELISA, we further showed disparity in differentiation grade and proliferation between tumours with varied cyclin D1/ER alpha content. In another fraction (9 out of 24) of the heterogeneous tumours, there was an inverse association between the ER alpha and Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha) suggesting that ER alpha was down-regulated during hypoxic conditions. These results were verified by culturing ER alpha breast cancer cell lines under hypoxic conditions showing a prominent down-regulation of the ER alpha. The two factors linked to ER alpha down-regulation can also be used to design new treatment approaches interfering with key proteins in these ER alpha regulatory pathways, thereby hopefully increasing the effect of anti-hormonal treatment.