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

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/ß-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.

DNA polymerase ζ deficiency causes impaired wound healing and stress-induced skin pigmentation.

DNA polymerase ζ (pol ζ) is a specialized enzyme important for DNA damage tolerance, facilitating synthesis past lesions caused by radiation or chemical damage. Here we report that disruption of Rev3l (encoding the catalytic subunit of pol ζ) in mouse epidermis leads to a defect in proliferation that impairs cutaneous wound healing. A striking increase in epidermal skin pigmentation accompanied both wound healing and UV irradiation in these mice. This was a consequence of stress-induced migration of Rev3l-proficient melanocytes to the Rev3l-defective epidermis. This pigmentation corresponded with p53 activation in keratinocytes and was absent in p53-negative areas of the epidermis. Expression of the kit ligand (Kitl) gene, a p53-controlled mediator of keratinocyte to melanocyte signaling, was enhanced during wound healing or following UV irradiation. This study extends the function of pol ζ to the process of proliferation during wound healing. Rev3l-deficient epidermis may be a useful mouse model system for examining communication between damaged keratinocytes and melanocytes, including signaling relevant to human disease.