HIC1 regulates tumor cell responses to endocrine therapies.

An intractable problem impeding breast cancer treatment by the most frequently prescribed endocrine therapy tamoxifen is the inevitable development of resistance, and the molecular mechanisms underlying this loss of responsiveness by breast cancers have been under intense investigation but are not yet fully elucidated. Our recent reports demonstrated that the tumor suppressor heavily methylated in cancers 1 (HIC1) plays an essential role in growth suppression mediated by external stimuli. We report here that novel tumor suppressor HIC1 is required for growth suppression by estrogen antagonists in breast cancer cells. We also find that HIC1 expression is dramatically induced by exposure to estrogen antagonists in sensitive cells, via a c-Jun N-terminal kinase 1 (JNK1) and prohibitin-mediated signaling pathway. This induction is lost in spontaneously antagonist-resistant breast cancer cells. Furthermore, reintroducing HIC1 into resistant breast cancer cells restored their sensitivity to the estrogen antagonists, indicating the existence of a novel regulatory mechanism for growth control of breast cancer cells.