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Functional interplay between ER and MAF transcription factors in breast cancer bone metastasis

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Universitat de Barcelona. Facultat de Biologia

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[eng] Metastatic breast cancer (BCa) is the leading cause of death in BCa patients. Current therapies for BCa aim at cell proliferation and, therefore, latent disseminated cells are able to escape treatment. For this reason, there is an urgent need to understand the molecular mechanisms by which BCa cells invade distant tissues to develop new therapeutic opportunities. It was recently discovered that the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) transcription factor drives specifically bone colonization in estrogen receptor (ER)-positive BCa patients. MAF was shown to transcriptionally regulate genes that support metastatic functions, thereby emerging as an attractive target for the prevention of BCa metastasis to the bone. However, the nuclear localization of MAF, its lack of enzymatic activity and its intrinsically disordered structure made this transcription factor a challenging therapeutic target and brought to the forefront the potential of MAF-transcriptionally controlled proteins as well as MAF-interacting partners to become pharmacological targets for the prevention of bone metastasis. For this reason, in the present thesis, we performed a proximity-dependent biotin identification (BioID) screen to identify MAF-interacting partners that may cooperate with this transcription factor to promote bone colonization. BioID proximity labeling captured the MAF interactome in BCa cells, mainly comprised of chromatin-remodeling proteins that may influence histone modification to generate transcriptionally active or repressive chromatin structures for gene expression regulation. Moreover, ER, the main driver of ER+ BCa, emerged as a MAF interactor. MAF-positive tumors treated with bisphosphonates, a major therapeutic option for the treatment of bone metastasis, were associated with increased adverse outcomes in premenopausal patients, thereby supporting a role for estrogen (E2), the main ER ligand, in the modification of MAF-positive tumors behavior. Given this observation, we considered the MAF-ER interaction of major interest and explored the molecular mechanisms underlying the cross-talk of both transcription factors. Gene expression analyses revealed a MAF-E2 signature, which suggested that MAF modulates the E2 response either by triggering a switch of target genes or by potentiating the expression of specific E2-responsive genes. Interrogation of the chromatin landscape in BCa cells led to the observation that MAF expression was associated with increased chromatin accessibility. Moreover, assessment of ER binding to chromatin showed an increase in ER recruitment to DNA regulatory regions depending on MAF presence. Thus, our results demonstrate that MAF recruits chromatin-remodeling proteins to generate accessible chromatin regions, which result in an increase of ER recruitment to chromatin potentially to induce the expression of genes that confer metastatic properties.

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Functional interplay between ER and MAF transcription factors in breast cancer bone metastasis