Interaction between Estrogen Receptors and p53: A Broader Role for Tamoxifen?

Tamoxifen is one of the most widely used anticancer drugs in the world. It is a safe drug with generally well-tolerated side effects and has been prescribed for the treatment of early-stage and advanced-stage or metastatic estrogen receptor α (ERα/ESR1)-positive breast cancer. Tamoxifen therapy also provides a 38% reduction of the risk of developing breast cancer in women at high risk. With the advent of newer medications targeting ERα-positive breast cancer, tamoxifen is now mainly used as adjuvant therapy for lower-risk premenopausal breast cancer and cancer prevention. It is widely accepted that tamoxifen as a selective estrogen receptor modulator exerts its therapeutic effect by competitively binding to ERα, leading to the recruitment of corepressors and inhibition of transcription of genes involved in the proliferation of breast cancer epithelium. As such, expression of ERα in breast tumors has been considered necessary for tumors to be responsive to tamoxifen therapy. However, ERα-independent effects of tamoxifen in various in vitro and in vivo contexts have been reported over the years. Importantly, the recent discovery that ERα and estrogen receptor β (ERβ/ESR2) can bind tumor suppressor protein p53 with functional consequences has provided new insights into the mechanisms underlying response to tamoxifen therapy and resistance. Furthermore, these findings have paved the way for broadening the use of tamoxifen by potentially repurposing it to treat triple negative (negative for ERα, human epidermal growth factor receptor 2, and progesterone receptor) breast cancer. Herein, we summarize these developments and discuss their mechanistic underpinnings and clinical implications.