Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

Abstract

Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.

Real-time in vivo imaging of p16Ink4areveals cross talk with p53

“…Ink4a expression in the mammary glands of p53 knockout mice (Zhang et al, 2008). Together, our finding may help to explain why mice doubly deficient for p53 and p16…”

Identification of fibroblast growth factor-8b target genes associated with early and late cell cycle events in breast cancer cells

“…Here, we identified particularly Plk1 and aurora kinase A as FGF-8b targets. Both kinases are overexpressed in a large number of human tumors including breast cancer, and for most tumor types overexpression is associated with poor prognosis (Otto et al, 2009;Schvartzman et al, 2010;Strebhardt and Ullrich, 2006;Zhang et al, 2004;Zhang et al, 2008). Silencing cyclin D1 in S115 cells abolished the inducing effect of FGF-8b (at 12 h) on Plk1 and reduced it on cyclin B1 and aurora kinase A protein suggesting that their induction by FGF-8b is dependent on or affected by cyclin D1.…”

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

“…Furthermore, the mouse model makes it evident that elevated expression of Aurora-A for a prolonged period is necessary for the development of mammary tumors. The concept gains credence in view of the earlier published studies that Aurora-A overexpression for a relatively limited time interval in mammary glands with wild-type p53 and p53-deficient genetic backgrounds induced ductal hyperplasia and atypical ductal hyperplasia, respectively (20,21). The fact that another transgenic mouse model expressing Aurora-A driven by MMTV promoter through five pregnancy cycles was reported to develop mammary tumors in 40% of mice on a p53 wild-type background and in 70% of mice on a p53-heterozygous background further corroborates the idea (22).…”

“…Aurora-A overexpression-mediated deregulation of oncogenic and tumor-suppressor pathways have been implicated in the induction of genomic instability in the Aurora-A transgenic mouse models (20,21). We thus assessed global genomic copy number alterations in BLG-Aurora-A transgenic mouse tumors by aCGH analysis to assess genomic rearrangements caused by BLG-Aurora-A transgene.…”

“…Aurora-A transgenic mice overexpressing the kinase in mammary tissues have been reported to yield distinct phenotypes in various experimental models. Mammary glands targeted Aurora-A overexpression induced by the Wap-Cre system through a single pregnancy cycle revealed hyperplasia after a short latency in p53 wild-type background and atypical ductal hyperplasia like precancerous lesions following longer latency in p53-deficient background (20,21). On the other hand, Aurora-A overexpression through five cycles of pregnancy under the regulation of mouse mammary tumor virus (MMTV) promoter in p53 wild-type background was reported to induce mammary tumors in 40% mice at 20 months of age and in 70% mice with p53-heterozygous background at 18 months of age (22).…”