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


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.

SUBMITTER: Shee K 

PROVIDER: S-EPMC5839765 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Shee Kevin K   Yang Wei W   Hinds John W JW   Hampsch Riley A RA   Varn Frederick S FS   Traphagen Nicole A NA   Patel Kishan K   Cheng Chao C   Jenkins Nicole P NP   Kettenbach Arminja N AN   Demidenko Eugene E   Owens Philip P   Faber Anthony C AC   Golub Todd R TR   Straussman Ravid R   Miller Todd W TW  

The Journal of experimental medicine 20180207 3


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 i  ...[more]

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