Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties. Cancer Res; 74(14); 3983-94. Ó2014 AACR.

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression

“…3B). Our results show that c-Jun knockdown reduced the invasion ability of non-stimulated cells, which is consistent with our previous results (11). These results suggest that c-Jun potentiates TNF␣-induced TNBC cell invasion.…”

“…Invasion Assay-Cells were serum-starved overnight after siRNA transfection and then treated with or without TNF␣ for 48 h. Invasion assays were conducted as previously described (11) but with the following modification. After treatment with TNF␣, cells were trypsinized and stained with propidium iodide and the number of apoptotic cells were determined by flow cytometry.…”

“…The activation of AP-1 can be regulated by multiple mechanisms, including dimer composition, post-translational modifications and interactions with ancillary proteins (9). Our recent studies showed that AP-1 proteins, mainly Fra-1 and c-Jun, are highly expressed in TNBC compared with other types of breast cancer (10,11), underscoring the importance of unraveling the AP-1 signaling pathway in TNBC.…”

Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim

“…The transcription factor activator protein 1 (AP-1) is a dimeric complex comprised of the Jun, Fos, activating transcription factor and musculoaponeurotic fibrosarcoma protein families (14), and it is involved in cellular proliferation, transformation and death (15). The AP-1 complex forms various combinations of heterodimers and homodimers, and this combination determines the genes that are regulated by AP-1 (16).…”

Induction of c-Jun Expression by Breast Cancer Anti-estrogen Resistance-3 (BCAR3) in Human Breast MCF-12A Cells

“…It is well-known that c-Jun is overexpressed and associated with human breast cancers and with model cell and animal systems, and also plays a critical role in ras transformation and TPA-mediated carcinogenesis [1,6,11,25,29,30]. Besides its oncogenic property, c-Jun is associated with anti-estrogen action in several ways.…”