Clathrin Heavy Chain Interacts With Estrogen Receptor α and Modulates 17β-Estradiol Signaling

17 beta-estradiol (E2)-induced signaling and control of estrogen receptor (ER)alpha degradation both play a major role in breast cancer cell proliferation. We recently reported the involvement of lysosomal function in both E2-dependent ER alpha breakdown and E2-induced cell proliferation and thus hypothesized a role for endocytic proteins in ER alpha signaling. An small interfering RNA screen identified proteins that regulate intracellular endocytic traffic and whose silencing alters E2-induced ER alpha degradation. One such protein was the clathrin heavy chain (CHC), whose role in E2: ER alpha signaling to cell proliferation is unknown. Here, we show that CHC physically interacts with ER alpha in the cytoplasm of breast cancer cells and regulates E2-induced cell proliferation. Surprisingly, the CHC: ER alpha interaction is required to sustain E2 signaling but is dispensable for ER alpha degradation. Our data also demonstrate that many membrane trafficking proteins contribute to the regulation of ER alpha degradation, thus unraveling the contribution of endocytic proteins in E2:ER alpha signaling.