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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA058030-07
Application #
2837667
Study Section
Special Emphasis Panel (ZRG2-ET-2 (04))
Program Officer
Yang, Shen K
Project Start
1992-08-07
Project End
2000-11-30
Budget Start
1998-12-25
Budget End
1999-11-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Weroha, S John; Li, Sara Antonia; Tawfik, Ossama et al. (2006) Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats. Carcinogenesis 27:491-8
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
Li, S A; Weroha, S J; Tawfik, O et al. (2002) Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation. J Endocrinol 175:297-305
Li, Jonathan J; Papa, Dan; Davis, Marilyn F et al. (2002) Ploidy differences between hormone- and chemical carcinogen-induced rat mammary neoplasms: comparison to invasive human ductal breast cancer. Mol Carcinog 33:56-65
Mesia-Vela, Sonia; Sanchez, Rosa I; Li, Jonathan J et al. (2002) Catechol estrogen formation in liver microsomes from female ACI and Sprague-Dawley rats: comparison of 2- and 4-hydroxylation revisited. Carcinogenesis 23:1369-72
Li, J J; Weroha, S J; Davis, M F et al. (2001) ER and PR in renomedullary interstitial cells during Syrian hamster estrogen-induced tumorigenesis: evidence for receptor-mediated oncogenesis. Endocrinology 142:4006-14
Liao, D Z; Hou, X; Bai, S et al. (2000) Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster. Carcinogenesis 21:2167-73
Li, J J; Hou, X; Banerjee, S K et al. (1999) Overexpression and amplification of c-myc in the Syrian hamster kidney during estrogen carcinogenesis: a probable critical role in neoplastic transformation. Cancer Res 59:2340-6
Li, J J; Hou, X; Bentel, J et al. (1998) Prevention of estrogen carcinogenesis in the hamster kidney by ethinylestradiol: some unique properties of a synthetic estrogen. Carcinogenesis 19:471-7
Li, S A; Liao, D Z; Yazlovitskaya, E M et al. (1997) Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage. Carcinogenesis 18:1375-80

Showing the most recent 10 out of 14 publications