Pregnancy provides significant protection against breast cancer development in women that give birth before the age of 20 years. Similarly, parous rats are refractory to chemically induced mammary tumorigenesis. The mechanisms by which parity affects mammary cancer incidents will be investigated by the investigator and coworkers in this proposal using the rat as a model. Pregnancy is characterized by elevated concentrations in serum of hormones that regulate the development of the mammary gland and affect mammary carcinogenesis. This proposal examines the hypothesis that these hormonal changes, along with changes in the levels of hormone and growth factor receptors in the mammary gland, played a decisive role in reducing mammary gland susceptibility to carcinogenesis.
In specific aim I, mammary tissue and isolated mammary epithelial cells from virgin rats previously treated with carcinogen, which are highly susceptible carcinogenesis, will be transplanted into gland-free pads of parous hosts, which are refractory to carcinogenesis, and vise versa to determine whether refractory mammary tissue becomes susceptible and if susceptible mammary tissue become refractory to carcinogenesis in an appropriate hormonal environment. In addition, isolated mammary tumor cells will be transplanted into gland-free fat pads of refractory and susceptible rats to determine whether the hormonal environment of both these groups of rats is capable of sustaining the growth of already established mammary tumors.
In specific aim II, the role of growth hormone (GH), prolactin (PRL) and ovarian steroids in mediating the parity-associated refractoriness to chemically induced carcinogenesis will be examined. Somatostatin analog and bromocriptine will be used to reduce the circulating concentrations of GH and PRL, respectively, in virgin rats to the concentrations in parous rats. GH and PRL will be administered in osmotic pumps to parous rats to obtain the concentrations in serum of virgin animals. The GH and PRL manipulations will be carried out in intact rats and ovariectomized animals, untreated or treated with constant dosage of 17beta-estradiol and/or progesterone. All these experimental groups and untreated control groups will be injected with carcinogen and tumor incidence compared.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071590-05
Application #
6173059
Study Section
Pathology B Study Section (PTHB)
Program Officer
Yang, Shen K
Project Start
1996-08-10
Project End
2002-09-30
Budget Start
2000-06-01
Budget End
2002-09-30
Support Year
5
Fiscal Year
2000
Total Cost
$346,188
Indirect Cost
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Thordarson, Gudmundur; Slusher, Nicole; Leong, Harriet et al. (2004) Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-alpha activation via the mitogen-activated protein kinase Breast Cancer Res 6:R423-36
Talamantes, F; Ortiz, R (2002) Structure and regulation of expression of the mouse GH receptor. J Endocrinol 175:55-9
Thordarson, G; Lee, A V; McCarty, M et al. (2001) Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats. Carcinogenesis 22:2039-47
Camarillo, I G; Thordarson, G; Moffat, J G et al. (2001) Prolactin receptor expression in the epithelia and stroma of the rat mammary gland. J Endocrinol 171:85-95
Thordarson, G; Van Horn, K; Guzman, R C et al. (2001) Parous rats regain high susceptibility to chemically induced mammary cancer after treatment with various mammotropic hormones. Carcinogenesis 22:1027-33
Rajkumar, L; Guzman, R C; Yang, J et al. (2001) Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. Proc Natl Acad Sci U S A 98:11755-9
Moffat, J G; Dao, H; Talamantes, F (2000) Alternative 5'-untranslated regions of mouse GH receptor/binding protein messenger RNA are derived from sequences adjacent to the major L2 promoter. J Endocrinol 167:145-52
Shyamala, G; Louie, S G; Camarillo, I G et al. (1999) The progesterone receptor and its isoforms in mammary development. Mol Genet Metab 68:182-90
Contreras, B; Talamantes, F (1999) Growth hormone (GH) and 17beta-estradiol regulation of the expression of mouse GH receptor and GH-binding protein in cultured mouse hepatocytes. Endocrinology 140:4725-31
Moffat, J G; Edens, A; Talamantes, F (1999) Structure and expression of the mouse growth hormone receptor/growth hormone binding protein gene. J Mol Endocrinol 23:33-44

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