Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer

Authors

Adelaide Young
Wen Bu
Weiyu Jiang
Amy Ku
Jyoti Kapali
Sagar Dhamne
Lan Qin
Susan G Hilsenbeck
Yi-Chieh Nancy Du
Yi Li

Publication Date

1-1-2022

Journal

Cancer Prevention Research

DOI

10.1158/1940-6207.CAPR-21-0031

PMID

34667127

PMCID

PMC8741732

PubMedCentral® Posted Date

7-1-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Apoptosis, Apoptosis Regulatory Proteins, Breast Neoplasms, Female, Humans, Mice, Proto-Oncogene Proteins c-bcl-2, Receptors, Estrogen, breast cancer, chemoprevention, mouse model, PIK3CA, venetoclax

Abstract

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. PREVENTION RELEVANCE: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.

Comments

Associated Data