Adenomyoepitheliomatous lesions of the mammary glands in transgenic mice with targeted PLAG1 overexpression.

PLAG1 proto-oncogene overexpression has been causally linked to multiple tumors, highlighting its broad tumorigenic relevance. Here, the oncogenic potential of PLAG1 in mammary gland tumorigenesis was investigated in PLAG1 transgenic mice. To target mammary glands, mice of 2 independent PLAG1 transgenic strains, PTMS1 and PTMS2, in which PLAG1 expression can be modulated by Cre-mediation, were crossed with MMTV-Cre transgenic mice, resulting in P1-MCre and P2-MCre offspring, respectively. Hundred percentage of P1-MCre female mice showed mammary gland hyperplasia, caused by adenomyoepithelial adenosis, at 8 weeks. The tumorigenic process could not be studied further in P1-MCre mice, because concomitant fast-growing salivary gland tumors required euthanasia. Sixteen percentage of P2-MCre females developed mammary gland adenomyoepitheliomas within 30-45 weeks, and none displayed concomitant salivary gland tumors. To further study mammary gland tumorigenesis in PTMS1-derived mice, intercrossing with WAP-Cre transgenic mice, resulting in P1-WAPCre mice, was performed to target PLAG1 expression more specifically to mammary glands. Eighty percentage of such mice developed adenomyoepitheliomas within 53-88 weeks. All PLAG1-induced adenomyoepitheliomas revealed expression upregulation of Igf2/H19, Dlk1/Gtl2, Igfbps and Wnt signaling genes (Wnt6, Cyclin D1). Collectively, these results establish the oncogenic potential of PLAG1 in mammary glands of mice and point towards contributing roles of Igf and Wnt signaling.