Abstract C069: Targeting the Bai1-driven signaling pathway as a therapeutic approach for breast cancer treatment

Abstract

Abstract Breast cancer is the most prevalent cancer among women globally, and it remains the second leading cause of cancer-related mortality in this group. Notably, breast cancer exhibits a survival disparity between black and white women, with black women experiencing higher mortality rates. While the reasons for this disparity are multifaceted, differences in molecular mechanisms and signaling pathways driving disease progression may contribute to the observed survival gap. In this study, we investigate the role of cancer cell fusion-driven tumor heterogeneity and metastasis as a potential explanation for the survival disparity in breast cancer. We hypothesize that the mechanism of breast cancer fusion involves Bai1 activation-driven induction of the Elmo1/Dock 180/Rac 1 signaling pathway. Elmo1 and Dock 180 are overexpressed in breast cancer cell lines and Elmo1/Dock 180 activation is associated with breast cancer metastasis. Targeting this pathway could prevent cancer cell fusion-driven metastasis and death. To test our hypothesis, we used non-metastatic and metastatic breast cancer cells isolated from black (HCC 1806, MDA-MB-157) and white (T47D, MDA-MB-231) women, as well as mesenchymal stem cells (MSCs) (hMSC4099, hMSC39334) as fusion partners. We used Elmo1 and Dock 180 shRNAs and a Rac1 inhibitor to analyze the role of Elmo1/Dock 180/Rac 1 signaling in breast cancer cell fusion. Fusion products were scored using the Cre/loxP system. We observed that breast cancer cells isolated from black women are more prone to fuse with MSCs than cells isolated from white women (P<0.05). knocking down Bai1 significantly reduced the frequency of fusion across all cell lines (P<0.05) and more significantly in the non-metastatic breast cancer cell line isolated from black women (P<0.001). A notable reduction in the frequency of fusion between breast cancer cells and MSCs was observed when Elmo1, Dock180, or Rac1 was inhibited (P<0.05). These results suggest that the Bai1/Elmo1/Dock180/Rac1 signaling plays an important role in cancer cell fusion. Targeting this mechanism could lead to new drug development tactics for cancer treatment. Citation Format: Oluwatoyin V. Odubanjo, Paul B. Tchounwou, Brenda M. Ogle, Felicite K. Noubissi. Targeting the Bai1-driven signaling pathway as a therapeutic approach for breast cancer treatment [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C069.