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Abstract Disclosure: S. Schmidt: None. C.A. Lange: Consulting Fee; Self; Consultant for Astrin. In the United States, 1 in 8 women will develop invasive BC within their lifetime. For Luminal breast cancer expressing steroid hormone receptors (SRs) for estrogen and progesterone (ER+/PR+), current standard of care targets ER with antagonists, such as tamoxifen, or blocks estrogen synthesis using aromatase inhibitors. Unfortunately, these endocrine therapies ultimately fail in up to 40% of patients with node positive status. Most endocrine resistant breast cancers retain expression of ER and PR, PGR being a key ER target gene. Two common mechanisms of resistance are ESR1 gene mutations, providing ligand-independent activation of ER, high expression of PR, and activation of oncogenic signaling pathways that circumvent therapies. These pathways include mitogen- and stress-induced signaling pathways (MAPKs, CDKs, PI3K/AKT). Notably, PR target genes encode many of the key components of oncogenic signaling pathways, such as ErbB family members and their ligands. Interestingly, PR can act to limit or divert ER-driven proliferation in hormone-sensitive breast cancer models. However, tumor-promoting actions of PR have been identified by the Lange lab and others. Constitutive ER/PR complexes cooperate at cancer-relevant target genes and both progestins and anti-progestins block estrogen-driven proliferation and survival. The Lange lab demonstrated that MAPK-activated phospho-PRs drive tamoxifen resistance and cancer stem cell expansion. Tumor heterogeneity underscores the need to target both hormone sensitive proliferating cells and non-proliferating cancer stem cells to avoid recurrence of newly resistant BC. A cytoplasmic adaptor molecule in the IGF/insulin signaling pathway, insulin receptor substrate-one (IRS-1), has been identified as a new possible target. We previously reported that IRS-1 is a ligand-independent phospho-PR target gene. Once expressed, IRS-1 forms a complex with ER/PR and is required for breast cancer stemness properties. We hypothesize that the transcriptional regulation of target genes by PR/ER/IRS-1 promotes endocrine resistance and supports stemness phenotypes in ER+ breast cancer. Further studies confirmed a close-proximity nuclear interaction between PR and IRS-1 upon estrogen (but not progestin) stimulation in additional models. This interaction was blocked upon IRS-1 inhibition or insulin treatment. Canonical cytoplasmic insulin/IR/IRS-1 signaling may sequester IRS-1 away from nuclear ER/PR complexes. Accordingly, insulin treatment dramatically reprogrammed the estrogen-driven transcriptome. Characterization of the signal-specific roles of cytoplasmic (insulin) or nuclear (estrogen) IRS-1 may reveal how altered SR signaling complexes contribute to endocrine resistance and may lead to new therapeutic targets for improved outcomes for women with endocrine resistant ER+ breast cancer. Presentation: 6/3/2024
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