title: Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen.
abstract: Purpose:Antiendocrine therapy remains the most effective treatment for estrogen receptor-positive (ER+) breast cancer, but development of resistance is a major clinical complication. Effective targeting of mechanisms that control the loss of ER dependency in breast cancer remains elusive. We analyzed breast cancer-associated fibroblasts (CAF), the largest component of the tumor microenvironment, as a factor contributing to ER expression levels and antiendocrine resistance.Experimental Design:Tissues from patients with ER+breast cancer were analyzed for the presence of CD146-positive (CD146pos) and CD146-negative (CD146neg) fibroblasts. ER-dependent proliferation and tamoxifen sensitivity were evaluated in ER+tumor cells cocultured with CD146posor CD146negfibroblasts. RNA sequencing was used to develop a high-confidence gene signature that predicts for disease recurrence in tamoxifen-treated patients with ER+breast cancer.Results:We demonstrate that ER+breast cancers contain two CAF subtypes defined by CD146 expression. CD146negCAFs suppress ER expression in ER+breast cancer cells, decrease tumor cell sensitivity to estrogen, and increase tumor cell resistance to tamoxifen therapy. Conversely, the presence of CD146posCAFs maintains ER expression in ER+breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146posCAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146negCAFs correlate with inferior clinical response to tamoxifen and worse patient outcomes.Conclusions:Our data suggest that CAF composition contributes to treatment response and patient outcomes in ER+breast cancer and should be considered a target for drug development.Clin Cancer Res; 23(7); 1710-21. ©2016 AACR.
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado. Peter.Kabos@ucdenver.edu heather.brechbuhl@ucdenver.edu.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Brechbuhl
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Jessica
authors.initials: J
authors.lastname: Finlay-Schultz
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Tomomi M
authors.initials: TM
authors.lastname: Yamamoto
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Austin E
authors.initials: AE
authors.lastname: Gillen
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cittelly
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Sams
authors.affiliation: Section of Hematology, Division of Hematology, Yale Cancer Center and Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Manoj M
authors.initials: MM
authors.lastname: Pillai
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Elias
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado.
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
authors.affiliation: Department of Pathology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Sartorius
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, Colorado. Peter.Kabos@ucdenver.edu heather.brechbuhl@ucdenver.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Kabos
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051929:CD146 Antigen / Q000235:genetics; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004967:Estrogens / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D011960:Receptors, Estrogen / Q000235:genetics*; D013629:Tamoxifen / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051929:CD146 Antigen; D004967:Estrogens; C497902:MCAM protein, human; D011960:Receptors, Estrogen; D013629:Tamoxifen