Abstract

An estimated 60-70 percent of human breast cancers are associated with sex hormone exposure. Approximately 60 percent of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. The possible biochemical roles of estrogens in the development of breast cancers remains to be fully elucidated. This research focuses on examination of the role of steroid hormones and estrogen biotransformations in breast cancer etiology. Our hypothesis is that alterations in the breast cancer tissue microenvironment can influence the extent of estrogen biosynthesis and metabolism, result in altered levels of hormonally active estrogens and their metabolites, and therefore influence breast tumor development and growth. Biochemical and molecular examination of this hypothesis in vitro will be performed in human patient breast tissue specimens and in several human breast cancer cell systems currently in use in our laboratories. These breast cell systems include immortalized transformed breast epithelial cells grown in monolayers on plastic or on extracellular matrix support (ecm such as Matrigel TM or collagen I) and cultures of human breast stromal cells isolated from breast cancer tissues or normal breast tissues. Traditional culturing of cells on plastic promotes maximal proliferation, while culturing cells on collagen or on Matrigel supports cell maintenance and subsequent differentiation.
The specific aims of the research on the various human breast cell systems are (1) to examine the extent of aromatase (CYP19) expression and cyclooxygenase (COX-1 and COX-2) expression in human breast cancer specimens, (2) to examine enzyme expression and the extent of formation of E2 in human breast cancer cell systems, (3) to examine the extent of formation of oxidative metabolites in human breast cancer cell systems, and (4) to determine the biological consequences of estrogen biosyntesis and metabolism in the human breast cell systems.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073698-02
Application #
2837729
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Poland, Alan P
Project Start
1997-12-18
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Ohio State University
Department
Type
Schools of Pharmacy
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210

  Publications

Balunas, Marcy J; Kinghorn, A Douglas (2010) Natural compounds with aromatase inhibitory activity: an update. Planta Med 76:1087-93
Brueggemeier, Robert W; Su, Bin; Darby, Michael V et al. (2010) Selective regulation of aromatase expression for drug discovery. J Steroid Biochem Mol Biol 118:207-10
Balunas, Marcy J; Su, Bin; Riswan, Soedarsono et al. (2009) Isolation and Characterization of Aromatase Inhibitors from Brassaiopsis glomerulata (Araliaceae). Phytochem Lett 2:29-33
Su, Bin; Darby, Michael V; Brueggemeier, Robert W (2008) Synthesis and biological evaluation of novel sulfonanilide compounds as antiproliferative agents for breast cancer. J Comb Chem 10:475-83
Davis, Danyetta D; Diaz-Cruz, Edgar S; Landini, Serena et al. (2008) Evaluation of synthetic isoflavones on cell proliferation, estrogen receptor binding affinity, and apoptosis in human breast cancer cells. J Steroid Biochem Mol Biol 108:23-31
Maffini, Maricel; Denes, Viktoria; Sonnenschein, Carlos et al. (2008) APRIN is a unique Pds5 paralog with features of a chromatin regulator in hormonal differentiation. J Steroid Biochem Mol Biol 108:32-43
Balunas, Marcy J; Su, Bin; Brueggemeier, Robert W et al. (2008) Natural products as aromatase inhibitors. Anticancer Agents Med Chem 8:646-82
Su, Bin; Tian, Ran; Darby, Michael V et al. (2008) Novel sulfonanilide analogs decrease aromatase activity in breast cancer cells: synthesis, biological evaluation, and ligand-based pharmacophore identification. J Med Chem 51:1126-35
Balunas, Marcy J; Su, Bin; Brueggemeier, Robert W et al. (2008) Xanthones from the botanical dietary supplement mangosteen (Garcinia mangostana) with aromatase inhibitory activity. J Nat Prod 71:1161-6
Su, Bin; Diaz-Cruz, Edgar S; Landini, Serena et al. (2008) Suppression of aromatase in human breast cells by a cyclooxygenase-2 inhibitor and its analog involves multiple mechanisms independent of cyclooxygenase-2 inhibition. Steroids 73:104-11

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