Joshi Shriya, Garlapati Chakravarthy, Nguyen Thi, Sharma Shaligram, Chandrashekar Darshan Shimoga, Bhattarai Shristi, Varambally Sooryanarayana, Krishnamurti Uma, Li Xiaoxian, Aneja Ritu
Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
Alkermes Inc, Waltham, MA, 02451, USA.
Cell Commun Signal. 2025 May 30;23(1):255. doi: 10.1186/s12964-025-02243-7.
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.
三阴乳腺癌（也称为雄激素受体三阴性（TN）乳腺癌）缺乏雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2（HER2）和雄激素受体（AR）的表达。雄激素受体三阴性乳腺癌表现出侵袭性特征且预后较差。由于缺乏治疗靶点的表达，雄激素受体三阴性乳腺癌患者的治疗选择有限。因此，雄激素受体三阴性乳腺癌患者需要新的治疗靶点和风险预测生物标志物。在本研究中，我们研究了驱动蛋白样蛋白1（KIFC1）在雄激素受体三阴性乳腺癌中的作用。我们发现C/EBPβ与KIFC1启动子结合并诱导其在雄激素受体三阴性乳腺癌细胞中的表达。值得注意的是，雄激素受体状态与KIFC1水平呈负相关。我们还发现雄激素受体转录抑制调节KIFC1表达的转录因子C/EBPβ。雄激素受体三阴性乳腺癌中雄激素受体表达的缺乏导致C/EBPβ上调，从而增强KIFC1表达。此外，雄激素受体三阴性乳腺癌中KIFC1的上调增加了癌细胞增殖并促进上皮-间质转化（EMT），导致雄激素受体三阴性乳腺癌的侵袭性特征。使用小分子抑制剂CW069抑制KIFC1可显著减小携带雄激素受体三阴性乳腺癌异种移植物的小鼠的肿瘤体积，但对三阴乳腺癌小鼠无效。这些数据表明，C/EBPβ和KIFC1的上调促成了雄激素受体三阴性乳腺癌的侵袭性特征和不良预后，有力地证明了使用驱动蛋白抑制剂靶向KIFC1可能是雄激素受体三阴性乳腺癌患者可行的治疗方法。
