Gustafsson Sheppard N, Heldring N, Dahlman-Wright K

Estrogen receptor-α (ERα) is initially overexpressed in two-thirds of all breast cancer and is involved in its development and proliferation. We previously reported that the RBCC protein interacting with PKC 1 (RBCK1) interacts with the ERα promoter and that RBCK1 expression positively correlates with ERα levels, expression of ERα downstream ...

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target genes and proliferation of breast cancer cells. Based on this, and that RBCK1 positively correlates with ERα expression in breast cancer samples, we propose RBCK1 as a potential therapeutic target in breast cancer acting as a modulator of ERα expression. To further explore this, the molecular mechanism by which RBCK1 regulates ERα expression has to be defined. Here, we show that ERα, RBCK1 and the RBCK1-interacting protein Protein Kinase C beta 1 (PKCβI) co-occupy a previously identified ERα binding region in the proximal ERα promoter. We describe a number of mechanistic details of this complex including that RBCK1 recruitment to the ERα promoter B is facilitated by ERα, which in turn facilitates PKCβI recruitment and PKCβI-dependent histone modifications. Furthermore, ERα regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ERα coactivator function of RBCK1 The interaction between RBCK1 and ERα was dependent on the E3 ubiquitin ligase domain of RBCK1 and the AF-1 domain of ERα. The ligand-binding function of ERα does not influence the interaction with RBCK1. In summary, our data provide insight into the molecular mechanism by which ERα expression is modulated in breast cancer cells.

Date: Oct. 05, 2012

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