Abstract C081: Exploring signaling pathways of tumor-nerve interactions in breast cancer

Abstract Abstract Introduction: Among the breast cancer, Triple Negative Breast Cancer (TNBC) is usually aggressive and invasive. In the United States, Black women have the highest TNBC incidence (25.2 per 100,000 women) which is almost double compared to other races (9∼13 per 100,000). Neurite outgrowth also known as autonomic nerve sprouting occurs in tumors and contributes to cancer progression and metastasis. Studies on neurite outgrowth in breast cancer (BCa) are limited, however, one study indicates that TNBC cells (4T1) secrete cytokines that induce neurite outgrowth in neurons, while reciprocally, neurons stimulate proliferation, migration, and survival of BCa cells via secretion of neurotransmitters. Snail is an important gene which regulates the epithelial-mesenchymal transition (EMT) process in which tumor cells at the invasive front undergo this transition to promote invasion, migration, and subsequent metastasis. We hypothesize that Snail expression will stimulate neurite outgrowth in BCa cells, particularly TNBC, through extracellular vesicles from cancer cells interacting with neurons. Methods: We collected conditioned media from BCa cells and isolated exosomes. Exosomal markers were detected using western blot. Additionally, we used Transmission Electron Microscopy (TEM) to observe the exosomes. Neurite outgrowth assays were then performed using conditioned medium or exosomes collected from MCF7 cells overexpressing Snail (MCF7 Snail) added to PC12 neuronal cells or Induced Pluripotent Stem Cells differentiated neuronal progenitor cells (NPC). Our previous results showed MCF7 overexpressing Snail eliminates ER-α which makes it a possible TNBC model. A proprietary protease inhibitor, mH4, which blocks Talin1 activation was employed to explore the inhibition of neurite differentiation. Results: First, Talin1 protein was found to be enriched in TNBC cancer cells BT549 and MDA-MB-231. Talin1 was also enriched in exosomes from MCF7 Snail cells. Increased neurite outgrowth was observed in PC-12 cells and NPC when cultured with conditioned medium or exosomes collected from MCF7 Snail cells compared to MCF7 Neo control. We found that mH4, Talin1 inhibitor antagonized Snail-mediated neurite outgrowth. Conclusion: We have uncovered a novel pathway whereby Snail transcription factor signaling in BCa mediates secretion of exosomes containing Talin1 in TNBC cells which promotes neurite outgrowth. Talin1 small molecule inhibitor shows promise for therapeutic targeting of tumor-nerve interactions in aggressive and invasive BCa including TNBC. GRANT SUPPORT: The authors acknowledge the use of core facilities supported by the National Institute on Minority Health and Health Disparities through grant number 5U54MD013376 and 1U54GM128729-01-DaCCoTA Scholars Program (PI: Rezvani) National Institute of General Medical Sciences (NIGMS). Citation Format: Bor-Jang Hwang, Gabrielle Edwards, Cole Davis Knoblich, Khosrow Rezvani, Valerie Odero-Marah. Exploring signaling pathways of tumor-nerve interactions in breast cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C081.