RT Journal Article
SR Electronic
T1 Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP 470
OP 481
DO 10.1158/1541-7786.MCR-15-0423
VO 14
IS 5
A1 Malorni, Luca
A1 Giuliano, Mario
A1 Migliaccio, Ilenia
A1 Wang, Tao
A1 Creighton, Chad J.
A1 Lupien, Mathieu
A1 Fu, Xiaoyong
A1 Hilsenbeck, Susan G.
A1 Healy, Nuala
A1 De Angelis, Carmine
A1 Mazumdar, Abhijit
A1 Trivedi, Meghana V.
A1 Massarweh, Suleiman
A1 Gutierrez, Carolina
A1 De Placido, Sabino
A1 Jeselsohn, Rinath
A1 Brown, Myles
A1 Brown, Powel H.
A1 Osborne, C. Kent
A1 Schiff, Rachel
YR 2016
UL http://mcr.aacrjournals.org/content/14/5/470.abstract
AB The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo. AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470–81. ©2016 AACR.This article is featured in Highlights of This Issue, p. 409