American Association for Cancer Research
15417786mcr150423-sup-156996_0_supp_3352033_42cq4z.ppt (254 kB)

Supplementary Figure 1 from Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance

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posted on 2023-04-03, 17:24 authored by Luca Malorni, Mario Giuliano, Ilenia Migliaccio, Tao Wang, Chad J. Creighton, Mathieu Lupien, Xiaoyong Fu, Susan G. Hilsenbeck, Nuala Healy, Carmine De Angelis, Abhijit Mazumdar, Meghana V. Trivedi, Suleiman Massarweh, Carolina Gutierrez, Sabino De Placido, Rinath Jeselsohn, Myles Brown, Powel H. Brown, C. Kent Osborne, Rachel Schiff

Genes up-regulated in Tam-R and putatively associated with EGF-induced ER binding sites (genes containing an AP-1 motif are shown in bold)


American Italian Cancer Foundation

Susan G. Komen for the Cure


Stand Up 2 Cancer


Cancer Center

the EIF/Lee Jeans Breast Cancer Research Program, Breast Cancer Research Foundation, Cancer Prevention Research Institute of Texas Baylor College of Medicine Comprehensive Cancer Training Program



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.

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