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<p>Quadruple-negative breast cancers (also known as AR-triple negative (TN) BC) lack the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and androgen receptor (AR). AR-TNBC exhibits aggressive characteristics and a poor prognosis. Because of the lack of expression of therapeutic targets, limited therapeutic options exist for patients with AR-TNBC. Hence, new therapeutic targets and risk-predictive biomarkers are required for patients with AR-TNBC. In this study, we investigated the role of kinesin-like protein 1 (KIFC1) in AR-TNBC. We found that C/EBPβ binds to the KIFC1 promoter and induces its expression in the AR-TNBC cells. Notably, AR status was negatively correlated with KIFC1 levels. We also found that AR transcriptionally repressed the transcription factor C/EBPβ, which regulates the expression of KIFC1. The lack of AR expression in AR-TNBC led to C/EBPβ upregulation, thereby enhancing KIFC1 expression. Moreover, upregulation of KIFC1 in AR-TNBC increased cancer cell proliferation and promoted epithelial-mesenchymal transition (EMT), contributing to the aggressive characteristics of AR-TNBC. Inhibiting KIFC1 using the small molecule inhibitor CW069 significantly reduced tumor volume in mice bearing AR-TNBC xenografts, but not in those with triple-negative breast tumors. These data suggest that upregulation of C/EBPβ and KIFC1 contributes to the aggressive characteristics and poor prognosis of AR-TNBC, providing strong evidence that targeting KIFC1 using kinesin inhibitors could be a viable therapeutic approach for patients with AR-TNBC.</p> Graphical Abstract <p></p>

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C/EBPβ increases tumor aggressiveness by enhancing KIFC1 expression in androgen receptor negative triple negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月30日

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  • Shriya Joshi,
  • Chakravarthy Garlapati,
  • Thi Nguyen,
  • Shaligram Sharma,
  • Darshan Shimoga Chandrashekar,
  • Shristi Bhattarai,
  • Sooryanarayana Varambally,
  • Uma Krishnamurti,
  • Xiaoxian Li,
  • Ritu Aneja

摘要

Quadruple-negative breast cancers (also known as AR-triple negative (TN) BC) lack the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and androgen receptor (AR). AR-TNBC exhibits aggressive characteristics and a poor prognosis. Because of the lack of expression of therapeutic targets, limited therapeutic options exist for patients with AR-TNBC. Hence, new therapeutic targets and risk-predictive biomarkers are required for patients with AR-TNBC. In this study, we investigated the role of kinesin-like protein 1 (KIFC1) in AR-TNBC. We found that C/EBPβ binds to the KIFC1 promoter and induces its expression in the AR-TNBC cells. Notably, AR status was negatively correlated with KIFC1 levels. We also found that AR transcriptionally repressed the transcription factor C/EBPβ, which regulates the expression of KIFC1. The lack of AR expression in AR-TNBC led to C/EBPβ upregulation, thereby enhancing KIFC1 expression. Moreover, upregulation of KIFC1 in AR-TNBC increased cancer cell proliferation and promoted epithelial-mesenchymal transition (EMT), contributing to the aggressive characteristics of AR-TNBC. Inhibiting KIFC1 using the small molecule inhibitor CW069 significantly reduced tumor volume in mice bearing AR-TNBC xenografts, but not in those with triple-negative breast tumors. These data suggest that upregulation of C/EBPβ and KIFC1 contributes to the aggressive characteristics and poor prognosis of AR-TNBC, providing strong evidence that targeting KIFC1 using kinesin inhibitors could be a viable therapeutic approach for patients with AR-TNBC.

Graphical Abstract