Control of Estrogen Production in Breast Cancer

Institution: Beckman Research Institute of the City of Hope
Investigator(s): Shiuan Chen, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1RB-0118 Award: $342,712
Award Type: Research Project Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1995)
Estrogens have a major effect on the development of breast cancer. About 60% of premenopausal and 75% of postmenopausal breast cancer patients have estrogen-dependent tumors. In estrogen-dependent breast tumors, estrogens induce the production of peptide growth factors which are responsible for the proliferative response of cancer cells. Aromatase is the enzyme that synthesizes estrogens, so an abnormality in the function of aromatase in breast cancer tumors must have a significant influence on tumor growth in breast cancer patients.

During this grant period, we will design and perform essential experiments to examine the function of aromatase in breast cancer and in surrounding fat cells and develop methods to regulate the function of aromatase in breast cancer patients, including evaluation of the amount of aromatase in breast cancer tumors and in the surrounding fat cells. In addition, experiments are being performed to determine the structural characteristics of aromatase and to provide insight into the interaction between aromatase and its inhibitors.

We anticipate that this research will have a direct impact on understanding the cause of estrogen-dependent breast cancer and on the prevention of further progression of cancer by controlling the function of aromatase with aromatase inhibitors. This research is relevant to two of the BCRP priority issues for the grant cycle, i.e., Pathogenesis and Prevention of Breast Cancer.


Final Report (1998)
The female hormone, estrogen, plays a major role in the development of breast cancer. Approximately 60% of premenopausal and 75% of postmenopausal patients have estrogen-dependent tumors. In estrogen-dependent breast tumors, estrogen stimulates the formation of growth factors that are essential for breast cancer growth. In cells, a protein called aromatase produces estrogen, and in breast cancer patients, tumors contain an abnormally high level of aromatase that generates a large amount of estrogen. The fat tissue in tumors is thought to play an essential role in producing estrogen. Therefore, we performed experiments to determine the impact of estrogen production in fat tissue on breast cancer development. In addition, we studied the control of estrogen formation in these tissues. Ultimately, we plan to develop a treatment to stop only the estrogen production in breast tumors, but not in normal tissues such as ovary. In this way, it may be possible to develop treatment modalities for managing breast cancer patients that employ tissue-selective estrogen reduction. This would not subject the patients to whole-body chemotherapy, which also has effects on normal tissues.

During the last three years, we studied how estrogen production in fat tissues is regulated. We found that the expression of aromatase in fat cells surrounding breast cancer cells is driven in a cAMP-dependent manner. Our experiments have revealed further that in benign tissue in the breast, estrogen formation is lower and controlled by glucocorticoids, and the cAMP-dependent mechanism is suppressed by a negative regulator in the human aromatase gene. We have identified and characterized the area in the human aromatase gene that has the negative regulatory action as well as the cAMP-regulatory segment of the gene. The results also suggest an interaction between the two regulatory regions. Our current hypothesis is that an unknown factor(s) that induces cAMP response, after estrogen exposure, is produced in cancer cells, and the control of aromatase expression/estrogen synthesis in surrounding fat cells is switched from a glucocorticoid-dependent to a cAMP-dependent mechanism. A characterization of the difference in the regulation of aromatase action in the cancerous and benign areas of the breast will increase our understanding the etiology and pathogenesis of breast cancer.

Gene regulation studies of aromatase expression in breast cancer and adipose stromal cells
Periodical:Journal of Steroid Biochemistry and Molecular Biology
Index Medicus: J Steroid Biochem Mol Biol
Authors: Zhou D, Zhou C, and Chen S
Yr: 1997 Vol: 61 Nbr: Abs: Pg:273-280

Aromatase and breast cancer
Periodical:Frontiers in Bioscience
Index Medicus: Front. Biosci.
Authors: Chen S
Yr: 1998 Vol: 3 Nbr: Abs: Pg:922-933

Characterization of a sliencer element in the human aromatase gene
Periodical:Archives of Biochemistry and Biophysics
Index Medicus: Arch Biochem Biophys
Authors: Zhou D, and Chen S
Yr: 1998 Vol: 353 Nbr: Abs: Pg:213-220

Identification of a promoter that controls aromatase expression in human breast cancer and adipose stromal cells
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Zhou D, Clarke P, Wang J, Chen S
Yr: 1996 Vol: 271 Nbr: 25 Abs: Pg:15191-15202

Identification and characterization of a cAMP-responsive element in the region upstream from promoter 1.3 of the human aromatase gene.
Periodical:Archives of Biochemistry and Biophysics
Index Medicus: Arch Biochem Biophys
Authors: Zhou D, Chen S
Yr: 1999 Vol: 371 Nbr: 2 Abs: Pg:179-90