Mouse ER+/PIK3CA H1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents

Elias E. Stratikopoulos, Nicole Kiess, Matthias Szabolcs, Sarah Pegno, Cheung Kakit, Xuewei Wu, Poulikos I. Poulikakos, Pamela Cheung, Hank Schmidt, Ramon Parsons

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R−induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER−independent PIK3CA-mutant breast cancer.

Original languageEnglish
Pages (from-to)47-59
Number of pages13
JournalOncogene
Volume38
Issue number1
DOIs
StatePublished - 3 Jan 2019

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