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Abstract
BackgroundEstrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. Protein kinases commonly activated in breast cancers phosphorylate steroid hormone receptors (SRs) and profoundly impact their activities.MethodsTo better understand the role of modified PRs in breast cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo. To complement this analysis, we assayed PR target gene regulation in T47D luminal breast cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation). Selected phospho-PR-driven target genes were validated by qRT-PCR and following RUNX2 shRNA knockdown in breast cancer cell lines. Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast cancer stem cell biology.ResultsPhospho-Ser294 PR species were abundant in a majority (54%) of luminal breast tumors, and PR promoter selectivity was exquisitely sensitive to posttranslational modifications. Phospho-PR expression and target gene programs were significantly associated with invasive lobular carcinoma (ILC). Consistent with our finding that activated phospho-PRs undergo rapid ligand-dependent turnover, unique phospho-PR gene signatures were most prevalent in breast tumors clinically designated as PR-low to PR-null (luminal B) and included gene sets associated with cancer stem cell biology (HER2, PAX2, AHR, AR, RUNX). Validation studies demonstrated a requirement for RUNX2 in the regulation of selected phospho-PR target genes (SLC37A2). In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast cancer stem cell fate.ConclusionsWe conclude that PR Ser294 phosphorylation is a common event in breast cancer progression that is required to maintain breast cancer stem cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2. Clinical measurement of phosphorylated PRs should be considered a useful marker of breast tumor stem cell potential. Alternatively, unique phospho-PR target gene sets may provide useful tools with which to identify patients likely to respond to selective PR modulators that block PR Ser294 phosphorylation as part of rational combination (i.e., with antiestrogens) endocrine therapies designed to durably block breast cancer recurrence.
Highlights
Estrogen and progesterone are potent breast mitogens
We conclude that progesterone receptor (PR) Ser294 phosphorylation is a common event in breast cancer progression that is required to maintain breast cancer stem cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2
A majority of breast tumors contain phospho-Ser294 PR We previously demonstrated functional roles for phosphorylation of PRs by mitogenic protein kinase pathways commonly elevated in breast cancers, including Mitogen-activated protein kinase (MAPK), cyclin-dependent kinases (CDKs), and CK2 [33, 51,52,53,54,55]
Summary
Estrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. The four major breast cancer subtypes (luminal A, luminal B, HER2-enriched, and basal-like) were identified and comprehensively analyzed across datasets that included mRNA expression, protein expression/ activation, microRNA expression, DNA copy number variation, DNA methylation, and exome sequencing [5] These results revealed that breast cancers display a wide range of tumor heterogeneity caused by alterations in multiple factors, including somatically mutated driver genes (e.g., TP53, PIK3CA, AKT1, CBFB, GATA3, and MAP3K1), gene amplifications (ERBB2), and hormonally regulated gene programs (driven primarily by estrogen, progesterone, and androgen steroids) [2, 3, 6]. A deeper mechanistic understanding of the complex molecular pathways that drive breast cancer progression and how they may emerge accompanied by more precise biomarkers is urgently needed to successfully impede tumor initiation, optimize and customize treatment strategies, as well as prevent disease progression while undergoing long-term (i.e., up to 10 years) endocrine therapy
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