In stress responses induced by a wide variety of DNA-damaging treatments and other cellular stressors, transcription of the bZip transcription factor ATF3 is robustly induced. Transgenic overexpression of the human ATF3 gene in keratin 5 (K5)-expressing murine epithelia led to a sparse-hair phenotype and aberrantly large hair follicles, but no skin tumors were observed in female BK5.ATF3 mice monitored for 15 months. However, when female BK5.ATF3 mice were bred and allowed to raise progeny, mammary carcinomas arose after one or two litters; mammary tumor incidence reached about 80% by 15 months of age. At the same age, mammary tumor incidence was less than 5% in non-transgenic, biparous littermates and in virgin BK5.ATF3 females. The majority of mammary tumors were carcinomas with prominent squamous metaplasia. Both K5 and ATF3 were expressed in myoepithelial cells of the transgenic mammary gland; by immunohistochemistry the majority of the transgenic ATF3 was confined to the nucleus. Mammary tumor cells expressed keratins K5, K6 and K8, suggesting that the target cells for tumorigenesis were either myoepithelial cells which subsequently exhibited transdifferentiation, or that relatively undifferentiated “stem-like” cells were the targets for malignant conversion. In addition, immunohistochemistry demonstrated overexpression of the tumor suppressor protein p53 in all BK5.ATF3 mammary carcinomas. Global gene expression analyses in human breast tumor samples have demonstrated substantial overexpression of ATF3. Taken together, these results suggest the possibility that ATF3 acts as an oncogene in the genesis of human breast cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]