Kinesin-like protein KIFC2 stabilizes CDK4 to accelerate growth and confer resistance in HR+/HER2– breast cancer
Shao-Ying Yang, … , A Yong Cao, Da-Qiang Li
Shao-Ying Yang, … , A Yong Cao, Da-Qiang Li
Published April 29, 2025
Citation Information: J Clin Invest. 2025;135(12):e183531. https://doi.org/10.1172/JCI183531.
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Research Article Cell biology Oncology

Kinesin-like protein KIFC2 stabilizes CDK4 to accelerate growth and confer resistance in HR+/HER2– breast cancer

Abstract

Hormone receptor–positive and human epidermal growth factor receptor 2–negative breast cancer (HR+/HER2− BC) is the most common subtype, with a high risk of long-term recurrence and metastasis. Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is a standard treatment for advanced/metastatic HR+/HER2– BC, but resistance remains a major clinical challenge. We report that kinesin family member C2 (KIFC2) was amplified in approximately 50% of patients with HR+/HER2– BC, and its high expression was associated with poor disease outcome, increased tumor protein p53 (TP53) somatic mutation, and active pyrimidine metabolism. Functional assays revealed that depletion of KIFC2 suppressed growth and enhanced sensitivity of HR+/HER2– BC cells to tamoxifen and CDK4/6 inhibitors. Mechanistically, KIFC2 stabilized CDK4 by enhancing its interaction with ubiquitin-specific peptidase 9 X-linked (USP9X). Importantly, reexpression of CDK4 in KIFC2-depleted cells partially rescued the decreased growth and increased sensitivity to tamoxifen and CDK4/6 inhibitors caused by KIFC2 depletion. Clinically, high KIFC2 mRNA expression was negatively associated with the survival rate of patients with HR+/HER2– BC who received adjuvant ET alone or in combination with CDK4/6 inhibitors. Collectively, these findings identify an important role for KIFC2 in HR+/HER2– BC growth and therapeutic resistance, and support its potential as a therapeutic target and predictive biomarker.

Authors

Shao-Ying Yang, Ming-Liang Jin, Lisa Andriani, Qian Zhao, Yun-Xiao Ling, Cai-Jin Lin, Min-Ying Huang, Jia-Yang Cai, Yin-Ling Zhang, Xin Hu, Zhi-Ming Shao, Fang-Lin Zhang, Xi Jin, A Yong Cao, Da-Qiang Li

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Figure 3

Knockdown of KIFC2 enhances the sensitivity of HR+/HER2– BC cells to the ET drug Tam and the CDK4/6 inhibitor Abema.

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Knockdown of KIFC2 enhances the sensitivity of HR+/HER2– BC cells to the...
(A and B) Cells stably expressing shNC or shKIFC2 (1 and 2) were treated with increasing concentrations of Tam (A) and Abema (B) for 72 hours. IC50 values were determined using CCK-8 assays. (C and D) Cells stably expressing shNC or shKIFC2 (1 and 2) were subjected to clonogenic survival assays with increasing concentrations of Tam (C) and Abema (D) for 7–9 days. Quantitative analyses are shown. (E and F) Cells stably expressing shNC or shKIFC2 1 were treated with vehicle, Tam combined with Abema (E), or Tam combined with Palbo (F) for 72 hours, then subjected to CCK-8 assays. (G and H) MCF7 cells with stable shNC or shKIFC2 1 expression were injected into BALB/c nude mice. After 18 days, mice were treated with vehicle, Tam (G), or Abema (H). Tumor growth rates are shown. (I) Expression status of KIFC2 in HR+/HER2– BC PDOs was assessed by IHC staining of postoperative pathological tissue slices from the same patients. Scale bars: 50 μm. (J and K) CellTiter-Glo 3D assays were conducted in HR+/HER2– BC PDOs treated with Tam, Abema, Palbo, or their combinations. Representative images (J) and quantitative data (K) are shown. Scale bars: 100 μm. Data are mean ± SD; A–F, I, and K, n = 3 per group; G and H, n = 6 per group. A and B: extra-sum-of-squares F test; C, D, G, and H: 1-way ANOVA; E, F, I, and K: 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.