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 1

KIFC2 is amplified and overexpressed in HR+/HER2– BC.

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KIFC2 is amplified and overexpressed in HR+/HER2– BC. (A) High-level am...
(A) High-level amplification of KIF members in over 5% of patients with HR+/HER2– BC in the FUSCC (n = 318), TCGA (n = 610), and METABRIC (n = 1,217) data sets. (B) Differences in mRNA expression levels of the KIF family members between HR+/HER2– BC tissues and normal samples in the FUSCC and TCGA data sets. (C) Venn diagram showing cross-analysis of the KIF family members, with both high-level amplification in over 5% patients in the FUSCC, TCGA, and METABRIC data sets and an upregulation in mRNA levels in the FUSCC and TCGA data sets. (D) CNA status of KIFC2 in patients with HR+/HER2– BC in the FUSCC, TCGA, and METABRIC data sets. (E) Analysis of mRNA levels of KIFC2 in HR+/HER2– BC cohorts from the FUSCC and TCGA data sets. Center lines represent the median. (F) Spearman’s correlation analysis of the relationship between the CNAs and mRNA expression levels of KIFC2 in HR+/HER2– BC from the FUSCC, TGCA, and METABRIC data sets. The black line indicates a correlation between CNA and mRNA; the center lines represent the median. (G) RT-qPCR analysis of KIFC2 mRNA levels in 15 pairs of HR+/HER2– BC tissues and matched noncancerous samples. The center lines represent the median. (H) Immunoblot analysis of KIFC2 protein levels in 15 pairs of HR+/HER2– BC tissues and matched noncancerous samples. The center lines represent the median. E: Mann-Whitney U test; G and H: 2-tailed Student’s t test. *P < 0.05; ***P < 0.001.