Abstract 5082: Loss of androgen receptor expression in triple negative breast cancer upregulates kinesin family member C1 (KIFC1) via increased β-catenin/TCF4 signaling

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, β-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, β-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, β-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 β-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. Citation Format: Benecia Jackson, Zahra Mesrizadeh, Robert Lou, Yate-Ching Yuan, Daniel Schmolze, Rania Bakkar, Jerneja Tomsic, Cristal Resto, Nancy Sanchez, Padmashree Rida, Shankar Subramaniam, Lucio Miele, Victoria Seewaldt, Nikita Jinna. Loss of androgen receptor expression in triple negative breast cancer upregulates kinesin family member C1 (KIFC1) via increased β-catenin/TCF4 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5082.