Activation of the Canonical Wnt/β-Catenin Pathway in ATF3-Induced Mammary Tumors

Abstract

Female transgenic mice that constitutively overexpress the transcription factor ATF3 in the basal epithelium of the mammary gland develop mammary carcinomas with high frequency, but only if allowed to mate and raise pups early in life. This transgenic mouse model system reproduces some features of human breast cancer in that about 20% of human breast tumor specimens exhibit overexpression of ATF3 in the tumor cells. The ATF3-induced mouse tumors are phenotypically similar to mammary tumors induced by overexpression of activating Wnt/β-catenin pathway genes. We now show that the Wnt/β-catenin pathway is indeed activated in ATF3-induced tumors. β-catenin is transcriptionally up-regulated in the tumors, and high levels of nuclear β-catenin are seen in tumor cells. A reporter gene for Wnt/β-catenin pathway activity, TOPGAL, is up-regulated in the tumors and several downstream targets of Wnt signaling, including Ccnd1, Jun, Axin2 and Dkk4, are also expressed at higher levels in ATF3-induced tumors compared to mammary glands of transgenic females. Several positive-acting ligands for this pathway, including Wnt3, Wnt3a, Wnt7b, and Wnt5a, are significantly overexpressed in tumor tissue, and mRNA for Wnt3 is about 5-fold more abundant in transgenic mammary tissue than in non-transgenic mammary tissue. Two known transcriptional targets of ATF3, Snai1 and Snai2, are also overexpressed in the tumors, and Snail and Slug proteins are found to be located primarily in the nuclei of tumor cells. In vitro knockdown of Atf3 expression results in significant decreases in expression of Wnt7b, Tcf7, Snai2 and Jun, suggesting that these genes may be direct transcriptional targets of ATF3 protein. By chromatin immunoprecipitation analysis, both ATF3 and JUN proteins appear to bind to a particular subclass of AP-1 sites upstream of the transcriptional start sites of each of these genes.

SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma

“…The induction of c-JUN expression and activity leads to tumor progression and development [34]. There are several AP-1 binding sites on SNAI2 promoter and SNAI2 is a direct transcriptional target of c-JUN in murine [35, 36]. In breast cancer, SNAI2 was expressed in an AP-1-dependent manner [37].…”

Prostate tumor overexpressed-1, in conjunction with human papillomavirus status, predicts outcome in early-stage human laryngeal squamous cell carcinoma

“…C-jun is a major transcriptional factors of the AP-1 complex and regulate a variety of cellular fates, including proliferation, differentiation and apoptosis [19]. The role of AP1 complexes in promoting cancer cell invasion and metastasis is well established [20, 21]. C-Jun is a transcription factor of the phosphatidylinositol 3-Kinase/Akt/mTOR signaling pathway, which is essential in a variety of cellular processes, including proliferation, differentiation, cancer stem cells biology and tumor initiation and propagation [22].…”

Expression of Wnt3 Activates Wnt/β-Catenin Pathway and Promotes EMT-like Phenotype in Trastuzumab-Resistant HER2-Overexpressing Breast Cancer Cells

“…In CRC, the activation of the Wnt/β-catenin pathway is mainly due to mutation or lost function of the APC gene or protein in a ligand independent manner (11). The activation of the Wnt pathway in breast cancer, however, is more likely due to co-expression of Wnt ligands and FZD receptors (11, 22-25). The Wnt ligands, Wnt1, Wnt3a, Wnt4, Wnt5a, and Wnt7b have been reported to mediate cell proliferation and migration through canonical or noncanonical Wnt pathways in breast cancer (11, 16, 24, 25, 26).…”