The research constitutes a two-pronged approach to the understanding of factors attending the development and sustaining of breast cancer. The first deals with metabolic events which may alter the hormonal milieu of the breast. One focus of the metabolic studies will be on fibrocystic disease, a four-fold risk factor for developing breast cancer. We plan to elucidate the origin of the extremely high levels of some steroids in human breast cyst fluid. For example, estriol-3-sulfate (E3-3S) is 100 times more concentrated in cyst fluid than the blood. Facilitated transport against a gradient or synthesis at the cyst lining from androgen precursors followed by preferential secretion of E3-3S into the cyst fluid are two pathways considered. Transport will be studied by infusing 3H-E3-3S into volunteers prior to aspiration of cyst fluid and comparing the tritiated components of the plasma and cyst fluids. Synthesis will be studied by introducing appropriate tritiated androgen precursors into the cyst fluid and determining the metabolites in the cysts aspirated 2 hrs. later. Also, the synthesis of E3-3S from androgen precursors will be studied in homogenates of cyst lining obtained at surgery. Two steroid metabolic pathways manifested by breast tumor in vitro, glucuronide formation and formation of long chain fatty esters will be explored further. We seek to quantify these pathways and seek correlations with parameters such as histopathology, receptor content of the tumor and the course of the disease. The second major thrust of the proposal is on mechanisms of estrogen action in the breast. We have found that the estrogen-stimulated rodent uterus responds early (30 min.) and later (2 hrs.) with induction respectively of a new hydrolase and of plasminogen activator. There is remarkable similarity between the human breast cancer cell line MCF-7 and the rodent uterus with regard to estrogen-stimulated induced proteins. We plan to assay the MCF-7 cultures for the uterine-like proteases, elucidate the biophysical characteristics and assess the consequences in terms of growth and viability of interfering with the elaboration or function of these proteases. These programs will 1) better define the hormonal milieu at the tissue level in an endocrine-related cancer and 2) assess macromolecular events which may relate to the ontogeny of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA002071-32
Application #
3163085
Study Section
Endocrinology Study Section (END)
Project Start
1977-12-01
Project End
1987-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
32
Fiscal Year
1985
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Levitz, M (1994) An overview of four plus decades of research in estrogens: a personal history. Steroids 59:456-62
Javitt, N B; Budai, K; Miller, D G et al. (1994) Breast-gut connection: origin of chenodeoxycholic acid in breast cyst fluid. Lancet 343:633-5
Finlay, T H; Tamir, S; Kadner, S S et al. (1993) alpha 1-Antitrypsin- and anchorage-independent growth of MCF-7 breast cancer cells. Endocrinology 133:996-1002
Levitz, M; Raju, U; Arcuri, F et al. (1992) Relationship between the concentrations of estriol sulfate and estrone sulfate in human breast cyst fluid. J Clin Endocrinol Metab 75:726-9
Kadner, S S; Katz, J; Finlay, T H (1992) Esterase-1: developmental expression in the mouse and distribution of related proteins in other species. Arch Biochem Biophys 296:435-41
Levitz, M; Raju, U; Boccardo, F et al. (1992) Steroid and cation correlations in human breast cyst fluid: preliminary findings. Cancer Detect Prev 16:57-9
Levitz, M; Raju, U; Katz, J et al. (1992) Esterase activity in human breast cyst fluid: associations with steroid sulfates and cations. Steroids 57:485-7
Katz, J; Levitz, M; Kadner, S S et al. (1991) Estradiol esters can replace 17 beta-estradiol in the stimulation of DNA and esterase synthesis by MCF-7 cells: a possible role for the estrogen-sensitive MCF-7 cell esterase. J Steroid Biochem Mol Biol 38:17-26
Banerjee, S; Katz, J; Levitz, M et al. (1991) Purification and properties of an esterase from human breast cyst fluid. Cancer Res 51:1092-8
Tamir, S; Kadner, S S; Katz, J et al. (1990) Regulation of antitrypsin and antichymotrypsin synthesis by MCF-7 breast cancer cell sublines. Endocrinology 127:1319-28

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