Abstract PO2-28-01: Deleting caveolin-1 in epithelial cells increases doxorubicin sensitivity in advance stage of breast cancer

Abstract

Abstract Caveolin-1 (Cav-1) is a lipid raft protein with a dual role, serving as a tumor suppressor and a promoter. Studies have unveiled Cav-1’s significance in breast cancer progression, impacting various aspects, including cell proliferation, apoptosis, autophagy, invasion, migration, and metastasis. Previously, our research demonstrated that the knockout (KO) of Cav-1 from epithelial cells reduced lung metastasis originating from primary tumors. In this study, we sought to investigate whether Cav-1 KO in epithelial cells increases sensitivity to doxorubicin (Dox) using both in vitro and in vivo studies. In our in vitro study, we observed reduced cell numbers in doxorubicin-treated Cav-1 KO cells compared to Dox-treated 4T1 cells (wild type). Flow cytometry-based cell cycle assay showed a significant increase in G2M phase arrest in Dox-treated Cav-1 KO cells compared with wild-type, confirming reduced cell growth and proliferation. To validate the increased sensitivity to Dox in vivo, we used a syngeneic tumor model using Cav-1 KO and 4T1 wild-type cells injected into the mammary fat of female Balb/c mice intraperitoneally. Subsequently, after one week of tumor cell injection, both groups received Dox at a dose of 8 mg/kg body weight/week for 3 weeks (a cumulative dose of 24 mg/kg body weight). Primary tumor sizes exhibited a significant reduction in Dox-treated mice, and this was further reduced in Cav-1 KO mice compared to the wild type. To quantify lung metastasis, we explanted the mice’s lungs and plated dissociated single cells in complete RPMI media supplemented with 6-thioguanine (6-GT). The number of 6-TG-resistant 4T1 metastatic cells was significantly lower in the lungs' suspension of Cav-1 KO mice treated with Dox compared to wild-type Dox-treated mice. Our findings confirm that knockout of Cav-1 increased the sensitivity of Dox treatment and inhibited breast cancer lung metastasis in Balb/c mice. Our ongoing analysis of the molecular pathways seeks to elucidate the underlying mechanism. Citation Format: Abhishek Pandit, Dhirendra Singh, Rashmi Pathak, Shilpa Thota, Joseph Francis. Deleting caveolin-1 in epithelial cells increases doxorubicin sensitivity in advance stage of breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-01.