ERα Micromap (µMap) proximity labeling reveals fulvestrant mechanisms.

Estrogen Receptor alpha (ERα) is the primary driver in ER+ breast cancer and can be targeted using small molecules such as fulvestrant, a selective estrogen receptor degrader (SERD). Despite being approved over two decades ago and used regularly in post-menopausal women, its precise anti-tumor mechanism remains unclear, with several reports showing efficacy without the requirement for ERα degradation. To investigate the molecular basis of fulvestrant's action, we employed split intein-based µMap photo-proximity labeling to profile ERα-associated interactions. Our findings reveal that fulvestrant displaces oncogenic interactions induced by estradiol and promotes ERα translocation to promyelocytic leukemia (PML) nuclear bodies, leading to altered transcriptional signatures and senescence. Overall, this study offers insights into SERD mechanism of action and establishes a framework for evaluating additional ERα modulators and degraders.