Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models

Authors

Amy T Ku
Adelaide I J Young
Ahmed Atef Ibrahim
Wen Bu
Weiyu Jiang
Meng Lin
Laterrica C Williams
Bryant Lee McCue
George Miles
Chandandeep Nagi
Fariba Behbod
Yi Li

Publication Date

2-6-2023

Journal

Cancer Prevention Research

DOI

10.1158/1940-6207.CAPR-22-0275

PMID

36343340

PMCID

PMC9905287

PubMedCentral® Posted Date

8-6-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Mice, Female, Hyperplasia, Thiazoles, Phosphoinositide-3 Kinase Inhibitors, Precancerous Conditions, Estrogen Receptor Modulators, Class I Phosphatidylinositol 3-Kinases, breast cancer, chemoprevention, mouse model, PIK3CA, alpelisib

Abstract

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.

PREVENTION RELEVANCE: PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.

Comments

Associated Data