Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen

Heather M. Brechbuhl, Jessica Finlay-Schultz, Tomomi M. Yamamoto, Austin E. Gillen, Diana M. Cittelly, Aik-Choon Tan, Sharon B. Sams, Manoj M. Pillai, Anthony D. Elias, William A. Robinson, Carol A. Sartorius, Peter Kabos

Research output: Contribution to journalArticle

39 Citations (Scopus)

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 CD146pos or CD146neg fibroblasts. RNA sequencing was used to develop a highconfidence 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. CD146neg CAFs 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 CD146pos CAFs maintains ER expression in ER+ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146neg CAFs 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.

Original languageEnglish
Pages (from-to)1710-1721
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number7
DOIs
Publication statusPublished - 2017 Apr 1
Externally publishedYes

Fingerprint

Estrogens
Fibroblasts
Breast Neoplasms
Tamoxifen
RNA Sequence Analysis
Neoplasms
Tumor Microenvironment
Therapeutics
Conditioned Culture Medium
Transcriptome
Estrogen Receptors
Research Design
Recurrence
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Brechbuhl, H. M., Finlay-Schultz, J., Yamamoto, T. M., Gillen, A. E., Cittelly, D. M., Tan, A-C., ... Kabos, P. (2017). Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clinical Cancer Research, 23(7), 1710-1721. https://doi.org/10.1158/1078-0432.CCR-15-2851

Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. / Brechbuhl, Heather M.; Finlay-Schultz, Jessica; Yamamoto, Tomomi M.; Gillen, Austin E.; Cittelly, Diana M.; Tan, Aik-Choon; Sams, Sharon B.; Pillai, Manoj M.; Elias, Anthony D.; Robinson, William A.; Sartorius, Carol A.; Kabos, Peter.

In: Clinical Cancer Research, Vol. 23, No. 7, 01.04.2017, p. 1710-1721.

Research output: Contribution to journalArticle

Brechbuhl, HM, Finlay-Schultz, J, Yamamoto, TM, Gillen, AE, Cittelly, DM, Tan, A-C, Sams, SB, Pillai, MM, Elias, AD, Robinson, WA, Sartorius, CA & Kabos, P 2017, 'Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen', Clinical Cancer Research, vol. 23, no. 7, pp. 1710-1721. https://doi.org/10.1158/1078-0432.CCR-15-2851
Brechbuhl HM, Finlay-Schultz J, Yamamoto TM, Gillen AE, Cittelly DM, Tan A-C et al. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clinical Cancer Research. 2017 Apr 1;23(7):1710-1721. https://doi.org/10.1158/1078-0432.CCR-15-2851
Brechbuhl, Heather M. ; Finlay-Schultz, Jessica ; Yamamoto, Tomomi M. ; Gillen, Austin E. ; Cittelly, Diana M. ; Tan, Aik-Choon ; Sams, Sharon B. ; Pillai, Manoj M. ; Elias, Anthony D. ; Robinson, William A. ; Sartorius, Carol A. ; Kabos, Peter. / Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 7. pp. 1710-1721.
@article{1eec09f6e2d346fa8e0c3f9c87c06398,
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 CD146pos or CD146neg fibroblasts. RNA sequencing was used to develop a highconfidence 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. CD146neg CAFs 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 CD146pos CAFs maintains ER expression in ER+ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146neg CAFs 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.",
author = "Brechbuhl, {Heather M.} and Jessica Finlay-Schultz and Yamamoto, {Tomomi M.} and Gillen, {Austin E.} and Cittelly, {Diana M.} and Aik-Choon Tan and Sams, {Sharon B.} and Pillai, {Manoj M.} and Elias, {Anthony D.} and Robinson, {William A.} and Sartorius, {Carol A.} and Peter Kabos",
year = "2017",
month = "4",
day = "1",
doi = "10.1158/1078-0432.CCR-15-2851",
language = "English",
volume = "23",
pages = "1710--1721",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen

AU - Brechbuhl, Heather M.

AU - Finlay-Schultz, Jessica

AU - Yamamoto, Tomomi M.

AU - Gillen, Austin E.

AU - Cittelly, Diana M.

AU - Tan, Aik-Choon

AU - Sams, Sharon B.

AU - Pillai, Manoj M.

AU - Elias, Anthony D.

AU - Robinson, William A.

AU - Sartorius, Carol A.

AU - Kabos, Peter

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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 CD146pos or CD146neg fibroblasts. RNA sequencing was used to develop a highconfidence 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. CD146neg CAFs 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 CD146pos CAFs maintains ER expression in ER+ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146neg CAFs 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.

AB - 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 CD146pos or CD146neg fibroblasts. RNA sequencing was used to develop a highconfidence 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. CD146neg CAFs 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 CD146pos CAFs maintains ER expression in ER+ breast cancer cells and sustains estrogen-dependent proliferation and sensitivity to tamoxifen. Conditioned media from CD146pos CAFs with tamoxifen-resistant breast cancer cells are sufficient to restore tamoxifen sensitivity. Gene expression profiles of patient breast tumors with predominantly CD146neg CAFs 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.

UR - http://www.scopus.com/inward/record.url?scp=85016953435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016953435&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-2851

DO - 10.1158/1078-0432.CCR-15-2851

M3 - Article

C2 - 27702820

AN - SCOPUS:85016953435

VL - 23

SP - 1710

EP - 1721

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -