Sahlberg, K. K. | bioRxiv Science

bioRxiv2020

Breast tumors escape endocrine therapy by ER-independent mechanisms triggered by the coordinated activities of HER2/HER3 and deacetylated FOXA1

Hormone-resistance in ER positive breast cancer is associated with high HER2 activity. Yet, the interplay between HER2 and FOXA1 in hormone resistant tumors is not elucidated. Now, we demonstrate that hormone resistant tumors have increased HER2 expression and that FOXA1 mediates the signals of HER2/3 in an Estrogen Receptor independent manner. Our in vitro and in vivo experiments reveal that HER2/HER3 triggers FOXA1 binding at chromatin regions of ER-regulated genes associated with poor prognosis, facilitating their expression and leading to ER-independent growth. Furthermore, our study supports that FOXA1 acetylated by the acetyltransferase EP300 is retained at ER chromatin regions, which enables ER function. By contrast, HER2/3 activation hinders FOXA1 acetylation and facilitates FOXA1 binding at non-ER interacting regions enriched towards poor prognosis genes. Moreover, FOXA1 deacetylation confers insensitivity to anti-ER drugs inhibitory effect in ER positive cells. These results elucidate how post-translational modifications of FOXA1 control transcription independently of ER in hormone-resistant tumors with enhanced HER2/3 signaling.

cancer biology↗

bioRxiv2020

Crosstalk between microRNA expression and DNA methylation drive the hormone-dependent phenotype of breast cancer

BackgroundAbnormal DNA methylation is observed as an early event in breast carcinogenesis. However, how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and have been shown to play key roles in various biological processes. Here, we integrate miRNA expression and DNA methylation at CpGs to study how miRNAs may affect the breast cancer methylome and how DNA methylation may regulate miRNA expression. ResultsmiRNA expression and DNA methylation data from two breast cancer cohorts were subjected to genome-wide correlation analysis. Clustering of the miRNA expression-DNA methylation association pairs significant in both cohorts identified distinct clusters of miRNAs and CpGs. These clusters recapitulated important biological processes associated with breast cancer pathogenesis. Notably, two major clusters were related to immune or fibroblast infiltration, hence identifying miRNAs associated with cells of the tumor microenvironment, while another large cluster was related to estrogen receptor (ER) signaling. Studying the chromatin landscape surrounding the CpGs associated with the estrogen-signaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2 and ER-alpha. Further, at the hub of the estrogen-cluster, we identified hsa-miR-29c-5p as negatively correlated with the mRNA and protein expression of the DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already in pre-invasive breast lesions and postulate that hsa-miR-29c-5p may trigger early event abnormal DNA methylation in ER positive breast cancer. ConclusionsWe describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes.

cancer biology↗