Abstract
6
Chromosomal instability (CIN) and aneuploidy are hallmark traits of human sporadic ductal carcinoma in-situ (DCIS) and invasive ductal breast cancer (IDBC). These distinguishing characteristics of human BC have been seen in 55-78% of the DCISs and in 85-92% of IDBCs. In the female ACI rat model, 100% incidence of multiple mammary neoplasms are induced by estrogens alone at essentially physiological, albeit constant serum concentrations of 17Β-estradiol (E2), ∼60-100 pg/ml. We have previously reported that DCISs and primary mammary tumors induced solely by estrogens frequently exhibit CIN and aneuploidy, 85% and 91%, respectively (Mol. Carcin. 2002). These findings provide an important clue as to the underlying mechanism(s) involved in the estrogen mediation of oncogenic processes in the breast. Our recent findings further demonstrate that solely E2-induced breast tumors in ACI rats remarkably resemble human DCIS and IDBC in other pertinent molecular features. Immunoprecipitation and Western blot analyses showed that Aurora A (AurA), a centrosomal kinase, is overexpressed in primary ACI rat breast tumors. Moreover, DCIS and primary murine breast tumors overexpressed γ-tubulin and centrin, and exhibited a 100% frequency in centrosome amplification with respect to number and volume, in both tumor stages. However, not all the cells within a given E2-induced DCIS exhibited centrosome amplification. All of these molecular alterations occur in human DCIS and IDBC, with a frequency of >80% and 100%, respectively. Our results show, for the first time, a direct association between estrogen action, via c-myc overexpression and amplification, and AurA kinase overexpression, centrosome amplification, CIN, and aneuploidy, as primary causative events leading to solely estrogen-induced mammary tumor development in the ACI rat. [Supported by NCI Grant RO1CA87591, 2T32ES07079 from NIEHS, NIH, and the MD/PhD Physician Scientist Program, KUMC].
[Proc Amer Assoc Cancer Res, Volume 45, 2004]
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