Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53^Y217C, a mouse model of the human hotspot mutant TP53^Y220C. DNA damage responses were lost in Trp53^Y217C/Y217C (Trp53^YC/YC) cells, and Trp53^YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53^-/- cells. Furthermore, Trp53^YC/YC male mice died earlier than Trp53^-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53^YC/YC thymic cells compared to Trp53^-/- cells. Surprisingly, we recovered only one Trp53^YC/YC female for 22 Trp53^YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53^YC/YC female embryos with exencephaly and the death of most Trp53^YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53^YC/YC weaned females in their progeny. Together, these data suggest that the p53^Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.

Approximately 40% ERα-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERα level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERα at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre⁺; Frmd8^fl/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 ERα. 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 ERα and UBE3A, and disrupts the interaction of UBE3A with ERα, thereby blocking UBE3A-mediated ERα 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 ERα and may control therapeutic sensitivity to tamoxifen in ERα-positive breast cancer patients.