The vast majority of epidemiological data indicate that major risk factors for human breast and endometrial cancer involve female sex hormones. Estrogens (Es) have been notably implicated in the etiology of these and other hormone-associated cancers in women. The study of E-induced neoplasms addresses the basic cellular and molecular mechanisms involving Es in carcinogenic processes in target tissues where no other exogenous agent is present. Recent findings by the applicant and colleagues have indicated that the inherent estrogenicity of these hormones is responsible for the development of E-induced renal carcinomas in hamsters. This represents a marked departure from most of the previous studies using this model. The applicant and colleagues propose an E-driven sequential multi-step scheme for E-induced carcinogenesis in the hamster kidney which involves cytotoxicity; reparative cell proliferation; aneuploidy; genomic (chromosomal) instability; inappropriate cell cycle gene, protooncogene, and suppressor gene expression; and gene amplification. To test further aspects of the multi-step scheme of E carcinogenesis in this model, the applicant proposes three specific aims.
Aim 1 is to determine whether the E-responsive genes which are elevated or overexpressed in early primary renal tumors relative to normal kidney are associated with chromosomes that are either gained or lost, and assess whether the observed chromosomal aberrations (chromatid and chromosome breaks) are nonrandom.
Aim 2 is to examine the role of estrogen receptor (ER), including its induced expression and possible mutations and variants in the E-induced renal tumor compared to normal kidney. These alterations in ER may contribute to growth advantages of early tumorous lesions and tumor foci.
Aim 3 is to determine the role of E in the regulation of G1 progression during E-induced carcinogenesis. Uncontrolled cell proliferation, frequently due to dysregulation of G1 progression of the cell cycle, is an important mechanism leading to malignancy. These studies of E-carcinogenesis in the hamster kidney will provide important insights for other E-induced cancer systems (e.g., breast and uterine tumor models) and contribute importantly to our understanding of the etiology of E-associated human cancers.
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