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The laboratory discovery of estrogen-induced apoptosis has been translated to treat antihormone resistant patients and to reduce the incidence of breast cancer in postmenopausal hysterectomized women with estrogen replacement therapy (ERT). The key step is the selection pressure exerted by long-term antiestrogen therapy or over 5 years of menopause to specific breast cancer cell populations that will be vulnerable to estrogen-induced apoptosis. However, the mechanisms underlying estrogen-induced apoptosis are currently unclear. At the cellular level, estrogen-induced apoptosis is dependent upon the estrogen receptor (ER), which can be completely blocked by antiestrogen ICI 182,780 or 4-hydroxytamoxifen (4-OHT). Knockdown of ER alpha, but not ER beta, through specific small interfering RNAs effectively blocks estrogen-induced apoptosis, indicating that the ER alpha subtype participates in apoptosis. Further examinations demonstrate that estrogen-induced apoptosis is due to accumulation of endoplasmic reticulum stress, inflammatory responses, and oxidative stress, which, in turn, activate the intrinsic mitochondrial pathway and the extrinsic death receptor pathway to complete the process. This contrasts with paclitaxel, which causes G2 arrest with immediate apoptosis. These stress responses are modulated by glucocorticoids and the c-Src inhibitor to block estrogen-induced apoptosis, but the mechanism for estrogen action is through a genomic pathway rather than a non-genomic pathway. In the nucleus, estrogen activates classic ERE-regulated endogenous genes, but the ERE transcriptional pathway does not directly participate in the estrogen-induced apoptosis in vitro or in vivo. Simultaneously, estrogen activates a non-classic transcriptional pathway involving the interaction of ER with transcription factors such as activator protein-1 (AP-1), which may regulate proliferation, stress responses, or apoptosis. Investigation of how AP-1 modulates the stress responses to trigger estrogen-induced apoptosis will ultimately uncover the mechanisms underlying estrogen-induced apoptosis.