PO.PS01.03 · 人群科学

三阴性乳腺癌中雄激素受体表达缺失通过增强beta-catenin/TCF4信号上调驱动蛋白家族成员C1（KIFC1）

Loss of androgen receptor expression in triple negative breast cancer upregulates kinesin family member C1 (KIFC1) via increased beta-catenin/TCF4 signaling

编号 5082 展板 22 时间 4/21 09:00–12:00 区域 Section 36 主讲 Benecia Jackson, BA

分会场 Etiology and Molecular Epidemiology Approaches to Decipher Cancer Disparities

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作者与单位 Authors & Affiliations

Benecia Jackson¹, Zahra Mesrizadeh², Robert Lou³, Yate-Ching Yuan⁴, Daniel Schmolze⁵, Rania Bakkar⁵, Jerneja Tomsic¹, Cristal Resto¹, Nancy Sanchez¹, Padmashree Rida⁶, Shankar Subramaniam⁷, Lucio Miele⁸, Victoria Seewaldt¹, Nikita Jinna¹

¹Department of Population Sciences, Beckman Research Institute of The City of Hope, Duarte, CA,²UC San Diego, La Jolla, CA,³Carrigent, Covina, CA,⁴Division of Translational Bioinformatics, City of Hope Comprehensive Cancer Center, Duarte, CA,⁵Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA,⁶Department of Science, Rowland Hall, Salt Lake City, UT,⁷Departments of Cellular & Molecular Medicine, Computer Science & Engineering, and Data Science, University of California San Diego, La Jolla, CA,⁸LSU Health New Orleans, New Orleans, LA

摘要 Abstract

中文摘要

四阴性乳腺癌（QNBC）是三阴性乳腺癌（TNBC）的一种侵袭性亚型，缺乏雄激素受体（AR）表达。QNBC具有高度增殖性，存在于超过半数的所有TNBC病例中。QNBC缺乏所有传统乳腺癌靶点（ER、PR、HER2、AR），且化疗具有高度细胞毒性。因此，对QNBC存在可干预且细胞相容性更好的靶点的未满足需求。驱动蛋白家族成员C1（KIFC1）是一种高度癌细胞特异性的微管结合蛋白，可阻止具有过多中心体（癌症标志）的癌细胞发生凋亡。临床前体外和体内证据表明，抑制KIFC1可根除癌细胞，同时保留正常健康细胞。在此，我们在体外和体内TNBC模型中以及通过GeoMx空间转录组分析，研究KIFC1作为QNBC潜在可干预生物标志物的作用。在TNBC细胞中敲低AR导致KIFC1、beta-catenin/TCF4表达和TCF4介导的转录上调，以及细胞增殖增加和凋亡减少。相反，在TNBC细胞中上调AR信号产生相反效果。QNBC细胞比AR阳性TNBC细胞对KIFC1抑制更敏感。我们在多个独立的公开可用乳腺癌患者队列中验证了AR基因表达与KIFC1、beta-catenin、TCF4和TCF4靶基因表达呈负相关。在来自Louisiana State University Health Sciences Center的大型TNBC组织集（n=250）中，相对于AR阳性TNBC样本，QNBC中的KIFC1表达上调。该组织集的空间转录组分析揭示，相对于AR高表达TNBC肿瘤，AR低表达肿瘤的上皮或间质区室中KIFC1、beta-catenin和TCF4表达上调。我们的研究结果提示，KIFC1可能通过增强beta-catenin/TCF4介导的信号在QNBC中上调，而抑制KIFC1可能抑制QNBC细胞增殖。总体而言，我们的工作提供了临床前证据，表明KIFC1可能作为一种潜在可干预的QNBC生物标志物，可改善对TNBC患者中侵袭性亚群的临床管理。

查看英文原文 English abstract

Quadruple negative breast cancer (QNBC) is an aggressive subtype of triple negative breast cancer (TNBC) that lacks androgen receptor (AR) expression. QNBC is highly proliferative and is present in more than half of all TNBC cases. QNBCs lack all traditional breast cancer targets (ER, PR, HER2, AR) and chemotherapy is highly cytotoxic. Thus, there is an unmet need for actionable and more cytocompatible targets for QNBC. Kinesin family member C1 (KIFC1) is a highly cancer-cell specific microtubule-binding protein that impedes cancer cells with excess centrosomes (hallmark of cancer) from undergoing apoptosis. Preclinical in vitro and in vivo evidence suggests that inhibition of KIFC1 eradicates cancer cells, while sparing normal, healthy cells. Here, we investigate KIFC1 as a potential actionable biomarker for QNBC in vitro and in vivo TNBC models as well as via GeoMx spatial transcriptomic analysis. Knockdown of AR in TNBC cells led to upregulation of KIFC1, beta-catenin/TCF4 expression, and TCF4-mediated transcription as well as increased cell proliferation and reduced apoptosis. Conversely, upregulation of AR signaling in TNBC cells produced the opposite effect. QNBC cells were more sensitive to KIFC1 inhibition than AR-positive TNBC cells. We validated in multiple independent publicly available breast cancer patient cohorts that AR gene expression negatively correlates with KIFC1, beta-catenin, TCF4, and TCF4-target gene expression. In a large TNBC tissue set (n=250) from Louisiana State University Health Sciences Center, KIFC1 expression is upregulated in QNBC relative to AR-positive TNBC samples. Spatial transcriptomic analysis of this tissue set revealed that KIFC1, beta-catenin, and TCF4 expression are upregulated in the epithelial or stromal compartments of AR-low relative to AR-high expressing TNBC tumors. Our findings suggest that KIFC1 may be upregulated in QNBCs via increased beta-catenin/TCF4-mediated signaling, and that inhibition of KIFC1 may suppress QNBC cell proliferation. Collectively, our work provides preclinical evidence that KIFC1 may serve as a potential actionable QNBC biomarker that could improve clinical management of an aggressive subpopulation of TNBC patients.

利益披露 Disclosure

B. Jackson, None.. R. Lou, None.. Y. Yuan, None.. D. Schmolze, None.. R. Bakkar, None.. J. Tomsic, None.. C. Resto, None.. N. Sanchez, None.. P. Rida, None.. S. Subramaniam, None.. V. Seewaldt, None.. N. Jinna, None.

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