ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer

Abstract

Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem-cell-related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.

MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression

“…To extend these results, we next focused on the ATF3 gene, which is activated by inflammation, interacts with NF-κB and promotes the progression of TNBC and other types of cancer 39 – 41 . Activating TFs, such as ATF3, heterodimerize with JUN and are also capable of binding to DNA in the absence of JUN 42 , 43 .…”

“…AP-1 associates with NF-κB p65 and regulates the NF-κB transactivation function 37 , 39 – 41 . We found that, like MUC1-C and NF-κB, the AP-1 JUN, FOS and ATF3 proteins occupy the SET1A and WDR5 pELSs and that silencing MUC1-C decreases their occupancy (Fig.…”

“…MUC1-C forms a nuclear complex with SET1A, WDR5 and AP-1 that drives an NF-κB inflammatory regulatory network. AP-1 associates with NF-κB p65 and regulates the NF-κB transactivation function 37,[39][40][41] . We found that, like MUC1-C and NF-κB, the AP-1 JUN, FOS and ATF3 proteins occupy the SET1A and WDR5 pELSs and that silencing MUC1-C decreases their occupancy (Fig.…”

In vivo validation of the functional role of MicroRNA-4638-3p in breast cancer bone metastasis

“…A study suggested that TGF-β1 could induce the expression of ATF3, and the induced ATF3 upregulated the expression of TGF-β1 in MCF-1OCA1a cells, thus forming a positive feedback loop for TGF-β signaling. Further, upregulated ATF3 was observed to be vital for TGF-β1 to increase the expression of its Epithelial-Mesenchymal Transition (EMT)-related genes, including snail, slug, and twist, hence increasing BC cell motility (Yin et al 2010;Ku et al 2020;Yan et al 2021). Cell proliferation (cyclin A1), invasion (matrix metalloproteinase 13; MMP13), and metastasis (Runx2) genes were found to be ATF3 target genes (Kwok et al 2009;Gokulnath et al 2017;Rohini et al 2019Rohini et al , 2021.…”

Transforming Growth Factor-β1-mediated Regulation of circ_DISP3 and ATF3 in Human Triple-negative Breast Cancer Cells

“…5 Such transcription factors are prevalent in BC, and one example is activating transcription factor-3 (ATF3). 6,7 ATF3 is a stress-inducible gene belonging to the activating protein 1 family, whose expression is associated with multiple diseases ranging from cancer to cardiac hypertrophy. 8 ATF3 has been implicated in regulating oncogenic activities through various mechanisms that either promote or suppress cancer progression depending on the cellular environment and the signaling pathways involved.…”