3470

Persistent Aurora (Aur) A and B over-expression, amplified centrosomes, chromosomal instability, and aneuploidy invariably occur together in a vast majority of human neoplasms. These molecular changes are frequently found (>80%) in human sporadic ductal carcinoma in-situ (DCIS), in primary invasive ductal breast cancers, and in 17β-estradiol (E2)-induced tumors in at least two animal models: the ACI rat mammary tumor and the Syrian hamster uterine-like stem cell tumors of the kidney (EUTK). Herein, we report that AurA and B are concomitantly over-expressed in early tumor lesions and in frank EUTKs. The over-expression of both kinases was markedly reduced in EUTKs from tumor-bearing hamsters subjected to either a 10-day E2 withdrawal period or treated for a similar period with Tamoxifen plus E2, when compared to EUTKs from hamsters treated with E2 alone. Cell proliferation, determined by Ki-67 labeling, was not significantly different among the EUTK treatment groups. These results indicate that both AurA and B are under estrogen control mediated by estrogen receptor α. To begin to assess, during E2-induced EUTK oncogenesis, whether the over-expression of AurA and B contributes to the deregulation of the centrosome cycle via their hyper-phosphorylation of specific protein substrates, we analyzed the protein expression of histone H3 (substrate for AurA and B) and TPX2 (substrate for AurA), a centrosomal protein that activates AurA, by immunohistochemistry and Western blot analysis. Our results show that, when compared to untreated age-matched controls and adjacent normal kidney tissue, the expression of histone H3 (3.7-fold) and TPX2 (1.6-fold) was significantly elevated in EUTKs. These data suggest that some Aur kinase mitotic substrates may contribute to the subsequent amplification of centrosomes leading to chromosome instability and aneuploidy, thus driving the oncogenic process elicited by estrogens. (Supported in part by NCI/NIH Grant RO1 CA102849).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA