AP-1 and Endocrine Resistance

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.

Source: Molecular Cancer Research - May 11, 2016 Category: Cancer & Oncology Authors: Malorni, L., Giuliano, M., Migliaccio, I., Wang, T., Creighton, C. J., Lupien, M., Fu, X., Hilsenbeck, S. G., Healy, N., De Angelis, C., Mazumdar, A., Trivedi, M. V., Massarweh, S., Gutierrez, C., De Placido, S., Jeselsohn, R., Brown, M., Brown, P. H., Os Tags: Oncogenes and Tumor Suppressors Source Type: research