ABSTRACT
Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.
Subject(s)
Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Mechanotransduction, Cellular/genetics , Transcriptome , p38 Mitogen-Activated Protein Kinases/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Case-Control Studies , Cell Line, Tumor , Cinnamates/pharmacology , Collagen/chemistry , Collagen/pharmacology , Drug Combinations , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Estradiol/pharmacology , Estrogen Receptor alpha/metabolism , Female , Fulvestrant/pharmacology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Histones/genetics , Histones/metabolism , Humans , Indazoles/pharmacology , Laminin/chemistry , Laminin/pharmacology , Mammary Glands, Human/drug effects , Mammary Glands, Human/metabolism , Mammary Glands, Human/pathology , Phenotype , Proteoglycans/chemistry , Proteoglycans/pharmacology , Tamoxifen/pharmacology , Tissue Culture Techniques , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus-negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series. Mol Cancer Ther; 17(9); 2060-71. ©2018 AACR.