RHAMM drives formation of polyploid cancer cells and confers resistance to ER-targeted therapy in breast cancer.

Endocrine resistance in ER+ breast cancer remains a major clinical challenge. Here, we identify RHAMM as a key driver of resistance by orchestrating polyploid cancer cell (PCC) formation. Single-cell transcriptomics uncovered a G2/M-enriched, RHAMM+ subpopulation in endocrine-resistant tumors. Mechanistically, RHAMM binds Septin9/10 to promote aberrant cytoskeleton polymerization, activating YAP independent of Hippo signaling, which induces cytokinesis failure and facilitates PCC generation. Concurrently, RHAMM destabilizes p21 mRNA, enabling cell cycle progression despite genomic instability. The RHAMM-p21 axis serves as a bypass mechanism supporting polyploidization. Upon endocrine treatment, RHAMM is transcriptionally up-regulated by Slug. Clinically, RHAMMhigh signatures are enriched in metastatic and recurrent ER+ tumors and correlate with poor prognosis, highlighting its therapeutic relevance. Importantly, targeting RHAMM or YAP abrogates PCC formation and restores fulvestrant sensitivity. These findings reveal RHAMM-mediated polyploidization as an adaptive mechanism underlying endocrine resistance, suggesting the therapeutic potential of targeting the RHAMM-YAP axis.