%0 Journal Article
%T Therapeutically targeting tumor microenvironment每mediated drug resistance in estrogen receptor每positive breast cancer
%A Anthony C.
%A Anthony C. Faber
%A Arminja N.
%A Arminja N. Kettenbach
%A Chao
%A Chao Cheng
%A Cheng
%A Demidenko
%A Eugene
%A Eugene Demidenko
%A Faber
%A Frederick S.
%A Frederick S. Varn
%A Golub
%A Hampsch
%A Hinds
%A Jenkins
%A John W.
%A John W. Hinds
%A Kettenbach
%A Kevin
%A Kevin Shee
%A Kishan
%A Kishan Patel
%A Nicole A.
%A Nicole A. Traphagen
%A Nicole P.
%A Nicole P. Jenkins
%A Owens
%A Patel
%A Philip
%A Philip Owens
%A Ravid
%A Ravid Straussman
%A Riley A.
%A Riley A. Hampsch
%A Shee
%A Straussman
%A Todd R.
%A Todd R. Golub
%A Todd W. Miller
%A Traphagen
%A Varn
%A Wei
%A Wei Yang
%A Yang
%J JEM | The Journal of Experimental Medicine
%D 2018
%R 10.1084/jem.20171818
%X Drug resistance to approved systemic therapies in estrogen receptor每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每sensitive and 每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.
%U http://jem.rupress.org/content/215/3/895