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<p>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<sup>+</sup>) 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月14日

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  • Yu Yan,
  • Athira Narayan,
  • Marzieh Mazinani,
  • Harumi Saeki,
  • Tao Huang,
  • Gabi Lofland,
  • Edward Gabrielson,
  • Leslie Cope,
  • Yasmine M. Kanaan,
  • Ali Afsari,
  • Tammey Naab,
  • Saraswati Sukumar,
  • Martin G. Pomper,
  • Vanessa F. Merino

摘要

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.