Sporadic breast cancer (BC) represents about 85-90 percent of all BC cases among women. Although the etiology of human BC is likely multi-factorial, it is increasingly evident that both endogenous estrogens (Es) and exogenously administered estrogenic agents (ERT, HRT) are related to increased BC risk. Presently, it is well established that Es, and to a lesser extent progestins, play a major role in the promotion of BC by virtue of their mitogenic activity. However, much less is known concerning the role of these hormones during the initiation process. To address this issue, a new approach is required. Our overall hypothesis is that E-induced mammary gland (MG) oncogenesis, a process we believe more closely resembles human BC, is primarily an ER-mediated process which is distinctly different from chemical carcinogenic processes at this tissue site in at least one pertinent aspect. The basis for this premise is our novel finding that E-induced carcinogenesis in female ACI rats results in a high frequency of aneuploidy in resulting MG tumors, similar to human BC. In contrast, chemically-induced (DMBA, NMU) rat MGTs are essentially all diploid. Moreover, based on preliminary data presented herein, is hypothesized that genomic instability is an early critical event in E carcinogenesis, and is not only an event related to tumor progression. To test this hypothesis, three specific aims are proposed. One. To test the hypothesis that genomic instability is an early, critical event in E carcinogenesis in the female ACI rat MGT model, and to elucidate the specific sequential chromosomal alterations during oncogenesis. Two. To test the hypothesis that, E-induced MG oncogenesis in female ACI rats is an ER-mediated process, and further characterize the MG ERalpha and PR during tumor development. Three. To provide evidence for the hypothesis that deregulation of cell cycle components may contribute to the genomic instability during E-induced oncogenesis and in primary MGTs. These studies should provide important insights regarding solely E-induced MG oncogenic processes in relation to human BC etiology.
| Li, Jonathan J; Weroha, S John; Lingle, Wilma L et al. (2004) Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats. Proc Natl Acad Sci U S A 101:18123-8 |
| Li, Jonathan J; Li, Sara Antonia (2003) Causation and prevention of solely estrogen-induced oncogenesis: similarities to human ductal breast cancer. Adv Exp Med Biol 532:195-207 |
