MAF and ERα Coordinately Drive Metastatic Programs in Breast Cancer

MAF amplification is associated with increased risk of metastasis in breast cancer (BCa) and can dictate response to antimetastatic therapy, especially in premenopausal women. Estrogen receptor–positive (ER⁺) BCa, which requires estrogen (E2) for progression and metastasis, displays diverse metastatic tendencies despite harboring the same oncogenic dependency, but the determinants behind these differing metastatic phenotypes are not well understood. In this study, Llorente, Blasco, Espuny, and colleagues sought to investigate a potential relationship between hormone signaling and MAF amplification in BCa metastasis and showed that MAF overexpression increased the rate of bone metastasis in ER⁺ BCa. Enhanced proliferation following E2 treatment was more pronounced in MAF-positive cells compared to mock-E2-treated cells, and isogenic cell line pairs derived from tumors formed in a conditional Maf overexpression BCa mouse model revealed that Maf-positive cells gave rise to more metastases and had a competitive advantage metastasizing to the bone compared to Maf-negative cells. Protein-protein interaction experiments revealed that MAF physically interacts with the ER transactivation domain and chromatin remodeling complexes in BCa, and transcriptomic analysis following manipulation of MAF and/or E2 treatment in BCa cells uncovered MAF/E2 dependent genes that were enriched for prometastatic pathways and correlated with MAF expression in BCa patient cohorts. Additionally, MAF and ER were found to share a common set of binding sites upon E2 treatment, including previously unknown ER binding sites near enhancers of MAF/E2-dependent prometastasis genes, and chromatin accessibility and deposition of active histone marks were also induced near MAF/E2 coregulated genes in MAF-positive cells upon E2 stimulation. The histone demethylase KDM1A was a high-confidence MAF interactor that has previously been linked to BCa, and knockdown of KDM1A diminished MAF/ER interactions as well as MAF/E2-dependent gene expression programs. Moreover, pharmacologic blockade of KDM1A blocked MAF-driven bone metastasis in vivo. In summary, this study revealed a novel KDM1A-dependent MAF-ER interaction that drives epigenomic reprogramming and metastasis in BCa and suggests that targeting KDM1A may be beneficial in MAF-amplified, ER⁺ BCa.

Llorente A, Blasco MT, Espuny I, Guiu M, Ballaré C, Blanco E, et al. MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis. Nat Cell Biol 2023 Nov 9 [Epub ahead of print].

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