We recently showed that the cellular gene at the mouse mammary tumor virus integration site in the int-5 locus is identical to the gene encoding aromatase (referred as int-5/aromatase). Aromatase catalyzes the conversion of androgens to estrogens. Aromatase levels are higher in breast tumors compared to normal tissue, indicating that the in situ aromatase/breast estrogen may play a role in breast cancer. No studies have demonstrated to direct involvement of mammary aromatasein mammary tumorigenesis. We have developed the int-5/aromaatase transgenic mice model, and demonstrated for the first time that increased mammary estrogenic activity due to the overexpression of int-5/aromatase in female mammary glands leads to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer, that may, in turn, increase the risk of developing aggressive breast cancer. In male transgenic mice, overexpression of int- t/aromatase leads to increased mammary growth and hyperplastic and dysplastic changes that are similar to gynecomastia (early male breast cancer). These observations indicate that increased mammary estrogen alone without the influence of circulating estrogen may be sufficient to induce early breast cancer. Using int-5/aromatase in vivo model we will: 1) examine the effect of increased mammary estrogen on the regulation of oncogenes, growth factors, and tumor suppressor genes implicated in breast cancer as will as genes involved in programmed cell death; 2) determine whether the synergistic interaction of estrogen (int-5/aromatase overexpression) with c-myc or TGFalpha or p53 (plus/minus, minus/minus) in transgenic crosses results in the acceleration and/or increase in the incidence of breast cancer, 3) investigate whether exposing int- 5/aromatase transgenic animals to carcinogens leads to an acceleration and/or increase in the incidence of breast cancer, and 4) determine whether blocking mammary estrogenic activity by therapeutic interventions in early stages of mammary development results in the prevention of preneoplastic/neoplastic changes that may, in turn, reduce the occurrence of breast cancer. The outcome of this study will help to understand the direct role of breast estrogen in the initiation and/or promotion of breast cancer, increased susceptibility to environmental carcinogens and may aid in designing therapeutic approaches for the prevention of estrogen- mediated breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075018-02
Application #
2733365
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Mohla, Suresh
Project Start
1997-07-15
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Nair, Hareesh B; Perla, Rao P; Kirma, Nameer B et al. (2012) Estrogen receptor-beta mediates the protective effects of aromatase induction in the MMTV-Her-2/neu x aromatase double transgenic mice. Horm Cancer 3:26-36
Kirma, Nameer B; Tekmal, Rajeshwar R (2012) Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations. J Steroid Biochem Mol Biol 131:76-82
Nair, Hareesh B; Kirma, Nameer B; Ganapathy, Manonmani et al. (2011) Estrogen receptor-? activation in combination with letrozole blocks the growth of breast cancer tumors resistant to letrozole therapy. Steroids 76:792-6
Chakravarty, Dimple; Tekmal, Rajeshwar Rao; Vadlamudi, Ratna K (2010) PELP1: A novel therapeutic target for hormonal cancers. IUBMB Life 62:162-9
Liu, Gui-Jian; Liu, Giujian; Wu, Yu-Sheen et al. (2008) Development of a high sensitivity, nested Q-PCR assay for mouse and human aromatase. Breast Cancer Res Treat 111:343-51
Tekmal, Rajeshwar Rao; Nair, Hareesh B; Perla, Rao P et al. (2007) HER-2/neu x aromatase double transgenic mice model: the effects of aromatase overexpression on mammary tumorigenesis. J Steroid Biochem Mol Biol 106:111-8
Tekmal, Rajeshwar Rao; Liu, Ya-Guang; Nair, Hareesh B et al. (2005) Estrogen receptor alpha is required for mammary development and the induction of mammary hyperplasia and epigenetic alterations in the aromatase transgenic mice. J Steroid Biochem Mol Biol 95:9-15
Luthra, Roopa; Kirma, Nameer; Jones, Jeremy et al. (2003) Use of letrozole as a chemopreventive agent in aromatase overexpressing transgenic mice. J Steroid Biochem Mol Biol 86:461-7
Streng, Tomi; Li, Xiangdong; Lehtoranta, Mari et al. (2002) Infravesical obstruction in aromatase over expressing transgenic male mice with increased ratio of serum estrogen-to-androgen concentration. J Urol 168:298-302
Kirma, N; Gill, K; Mandava, U et al. (2001) Overexpression of aromatase leads to hyperplasia and changes in the expression of genes involved in apoptosis, cell cycle, growth, and tumor suppressor functions in the mammary glands of transgenic mice. Cancer Res 61:1910-8

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