Estrogen receptors and their downstream targets in cancer.

Estrogen has crucial roles in the proliferation of cancer cells in reproductive organs such as the breast and uterus. Estrogen-stimulated growth requires two estrogen receptors (ERalpha and ERbeta) which are ligand-dependent transcription factors. High expression of ERs is observed in a large population of breast tumors. In addition, the positive expression of ERs correlates with well-differentiated tumors, a favorable prognosis, and responsiveness to an endocrine therapy with anti-estrogen drugs in patients with breast cancer. Transcription activities of ERs can be regulated by interacting proteins such as coactivators and kinases as well as ligand-binding. Moreover, ER isoforms lacking an ability to transactivate are involved in breast cancer. Downstream target genes of ERs have important roles in mediating the estrogen action in breast cancer. We have isolated and characterized several novel estrogen-responsive genes to clarify the molecular mechanism of the estrogen action in target cells. Among these genes, the estrogen-responsive finger protein (Efp) was found to be highly expressed in breast cancer. Efp as a ubiquitin ligase (E3) is involved in the proteasome-dependent degradation of the 14-3-3sigma protein, one of cell cycle brakes, this degradation resulting in the promotion of breast cancer growth. A full understanding of the expression and function of ERs and their target genes could shed light on how estrogen stimulates the initiation and promotion of cancer, providing a new approach to diagnose and treat cancer.