CRYβB2 is a biomarker for poor prognosis and response to CDK4/6 inhibitors in breast cancer

Breast cancer mortality is higher in African American (AA) women than in European American women, but the molecular mechanisms remain poorly understood. Previously, we showed that β-crystallin B2 (CRYβB2) is upregulated in AA breast tumors and promotes oncogenesis via nucleolin (NCL) activation. Presently no biomarkers, other than estrogen receptor (ER)/progesterone receptor (PR) expression, are used to prescribe cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) for women with hormone receptor positive (HR+) metastatic breast cancer. Here, we show that CRYβB2 overexpression drives cell cycle progression and CDK4/6 pathway activation in premalignant, ductal carcinoma in situ (DCIS), triple-negative breast cancer (TNBC), and ER⁺ breast cancer models. Targeting CRYβB2 or NCL reduced CDK4, cell division cycle 25 A (Cdc25a), and phosphorylated Rb (ppRb) levels. Tumors expressing CRYβB2 were selectively sensitive to the CDK4/6 inhibitor palbociclib, with CRYβB2 expression inversely correlating with IC₅₀ values. Knockdown of CRYβB2 conferred resistance, whereas NCL knockout or treatment with the NCL aptamer AS-1411 sensitized cells to palbociclib. In TNBC and ER+ tumors of AA patients, high CRYβB2 expression correlated with CDK4/pRb activation and decreased survival in TNBC. These results indicate that CRYβB2 drives CDK4/6 activation and may serve as a prognostic biomarker and predictor of response to palbociclib therapy.