Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism

Approximately 40% ERa-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERa level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERa at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre+; Frmd8fl/fl; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ERa. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1. On the other hand, FRMD8 interacts both with ERa and UBE3A, and disrupts the interaction of UBE3A with ERa, thereby blocking UBE3A-mediated ERa degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ERa and may control therapeutic sensitivity to tamoxifen in ERa-positive breast cancer patients. Overall design: Four mice mammary tumors at endpoint (17-18 weeks) from the MMTV-Cre- and MMTV-Cre+ models were harvested and analyzed using 10x Genomics.Single-cell RNA-seq libraries were prepared using the Chromium Single Cell 3' Reagent Kits v3 (10x Genomics) , according to the manufacturer's instructions.