Molecular mechanisms of estrogen receptor β-induced apoptosis and autophagy in tumors: implication for treating osteosarcoma

The estrogen receptors alpha (ER alpha) and beta (ER beta) are located in the nucleus and bind to estrogen to initiate transcription of estrogen-responsive genes. In a variety of tumor cells, ER beta has been shown to be a tumor suppressor. In particular, ER beta has anti-proliferative effects in osteosarcoma cells. Additionally, ER beta has been proven to regulate the apoptosis-related molecules IAP, BAX, caspase-3, and PARP, and to act on the NF-kappa B/BCL-2 pathway to induce apoptosis in tumors. Moreover, ER beta can regulate the expression of the autophagy associated markers LC3-I/LC-3II and p62 and induce autophagy in tumors by inhibiting the PI3K/AKT/mTOR pathway and activating the AMPK pathway. Here, we review the molecular mechanisms by which ER beta induces apoptosis and autophagy in a variety of tumors to further delineate more specific molecular mechanisms underlying osteosarcoma tumorigenesis and pathogenesis. Considering the broad involvement of ER beta in apoptosis, autophagy, and their interaction, it is plausible that the critical role of ER beta in inhibiting the proliferation and metastasis of osteosarcoma cells is closely related to its regulation of apoptosis and autophagy.