Abstract

Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ /HER2-) breast cancer is the most common subtype in females, frequently challenged by resistance to endocrine therapy and CDK4/6 inhibitors. Here we show that N-acetylneuraminate synthase (NANS) is significantly upregulated in female HR+ /HER2- breast cancer patients, inversely correlating with patient prognosis. Functionally, NANS promotes tumor growth and confers resistance to tamoxifen and CDK4/6 inhibitors independently of its canonical enzymatic activity. Mechanistically, NANS recruits ubiquitin-specific protease 7 (USP7) to deubiquitinate and stabilize large tumor suppressor kinase 2 (LATS2), leading to canonical Hippo pathway activation and upregulation of estrogen receptor α and CDK4. Reintroducing LATS2 into NANS -depleted cells partially rescues the impaired growth-promoting and drug-resistant phenotypes in vitro and in vivo. Furthermore, the clinical relevance of the NANS-USP7/LATS2 axis is confirmed in patient-derived female HR+ /HER2- breast cancer samples. Together, our findings unveil an enzymatic activity-independent role for NANS in driving therapy resistance, nominating it as a promising therapeutic target.