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

Cancer Prev Res (Phila). 2022 Jan;15(1):3-10. doi: 10.1158/1940-6207.CAPR-21-0031. Epub 2021 Oct 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Breast Neoplasms* / pathology
  • Female
  • Humans
  • Mice
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Estrogen


  • Apoptosis Regulatory Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Estrogen