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J Exp Med. 2018 Mar 5;215(3):895-910. doi: 10.1084/jem.20171818. Epub 2018 Feb 7.

Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer.

Author information

1
Department of Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH.
2
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH.
3
Department of Biochemistry and Cell Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH.
4
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN.
5
Research Medicine, Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN.
6
VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA.
7
Broad Institute of MIT and Harvard, Cambridge, MA.
8
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
9
Department of Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH todd.w.miller@dartmouth.edu.
10
Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH.

Abstract

Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen-sensitive and -resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.

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