title: Integration of molecular profiling and chemical imaging to elucidate fibroblast-microenvironment impact on cancer cell phenotype and endocrine resistance in breast cancer.
abstract: The tumor microenvironment is known to play a key role in altering the properties and behavior of nearby cancer cells. Its influence on resistance to endocrine therapy and cancer relapse, however, is poorly understood. Here we investigate the interaction of mammary fibroblasts and estrogen receptor-positive breast cancer cells in three-dimensional culture models in order to characterize gene expression, cellular changes, and the secreted protein factors involved in the cellular cross-talk. We show that fibroblasts, which are the predominant cell type found in the stroma adjacent to the cancer cells in a tumor, induce an epithelial-to-mesenchymal transition in the cancer cells, leading to hormone-independent growth, a more invasive phenotype, and resistance to endocrine therapy. Here, we applied a label-free chemical imaging modality, Fourier transform infrared (FT-IR) spectroscopic imaging, to identify cells that had transitioned to hormone-independent growth. Both the molecular and chemical profiles identified here were translated from cell culture to patient samples: a secreted protein signature was used to stratify patient populations based on gene expression and FT-IR was used to characterize breast tumor patient biopsies. Our findings underscore the role of mammary fibroblasts in promoting aggressiveness and endocrine therapy resistance in ER-positive breast cancers and highlight the utility of FT-IR for the further characterization of breast cancer samples.
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Holton
authors.affiliation: Departments of Molecular and Integrative Physiology, Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Bergamaschi
authors.affiliation: Departments of Molecular and Integrative Physiology, Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America; University of Illinois Cancer Center, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America; Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America; University of Illinois Cancer Center, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America; Departments of Mechanical Science and Engineering, Electrical and Computer Engineering, and Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhargava
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D006728:Hormones / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000473:pathology; D057054:Molecular Imaging; D010641:Phenotype; D011379:Prognosis; D017550:Spectroscopy, Fourier Transform Infrared; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D006728:Hormones