Abstract 6094: Caveolin-1 modulates stemness and chemosensitivity in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of BC, characterized by a therapy-refractory phenotype, higher propensity to early metastases, and worse prognosis. TNBC has a high expression of cancer stem-like cells (CSC), contributing to a poor clinical outcome. Notably, an upregulation of caveolin-1 (CAV-1), a major structural protein of caveolae within the plasma membrane, is associated with TNBC. In agreement, the Kaplan-Meier survival analysis predicted that patients with high CAV-1 expression have a significantly worse survival than those with low expression. Consistently, immunoblot analysis of PDX tumor samples revealed inter-tumor variation with high CAV-1 expression, supporting the role of dysregulated CAV-1 expression in TNBC progression. Previously, we have shown that CAV-1 knockout (Cav-1 KO) mitigated BC metastasis to the lungs via integrin alpha3 in a 4T1 syngeneic 4T1-murine model of TNBC. Upon further investigation, we observed a significant downregulation of pluripotent transcription factors such as SOX2, OCT-4, and NANOG when CAV-1 was depleted in mouse 4T1 and human SUM159PT cells. We hypothesized that CAV-1 regulates TNBC stemness through focal adhesion kinase (FAK)/ c-Myc signaling. Consistently, depletion of CAV-1 altered the levels of pY397FAK and c-Myc, confirming CAV-1-dependent suppression of CSC-like traits to be associated with FAK/c-Myc signaling. Next, we observed that CAV-1 KO cells exhibited enhanced chemosensitivity to paclitaxel (PTX) as compared to the corresponding 4T1 control cells (PTX IC50: 24.51nM in Cav-1 KO vs 30.82nM in 4T1 at 48h). The observed chemosensitivity was due to the downregulation of multidrug resistant protein 1 (MRP1/ABCC1) and P-glycoprotein (ABCB1). Importantly, CAV-1 expression was significantly higher in PTX-resistant human Pac200 cells as compared to the naïve SUM159PT cells. Collectively, these findings indicate that CAV-1 loss impairs major drug efflux pathways and promotes chemosensitivity. Overall, our study proposed a putative role for CAV-1 in TNBC stemness and multidrug resistance through FAK/c-Myc dependent modulation of the stemness pathway and ABC efflux transporters. Therefore, targeting CAV-1 provides a therapeutic strategy to enhance chemotherapy efficacy and overcome drug resistance in TNBC. Since CAV-1 lacks enzymatic activity or ligand-binding pockets, small-molecule targeting may not be a feasible approach. Hence, selective degradation of Cav-1 by (CAV-1)targeting PROTAC offers an innovative first-in-class therapeutic strategy to abrogate cancer stemness and effectively treat metastatic TNBC. Citation Format: Shreya Pokharel, Naveen Chintala Ramulu, Biplov Sapkota, Dhirendra Pratap Singh, Abhishek Pandit, Shilpa Thota, Rizwana Begum, Shobhit Srivastava, Yuxio Yo, Shang Su, Dayanidhi Raman, Joseph Francis. Caveolin-1 modulates stemness and chemosensitivity in triple negative breast cancer 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 6094.