Michael F. Press, MD, PhD
Harold E. Lee Chair in Cancer Research
2012-2013 BCRF Project:
(made possible by generous support from Bloomingdale's)
Norris Comprehensive Cancer Center
University of Southern California
Los Angeles, California
Dr. Press's team has identified genetic alterations in selected estrogen receptor coactivator/corepressor genes. These genetic alterations include both changes in gene copy number (gene amplification) and in genetic sequence. These researchers have shown that somatic mutations identified in two of the coactivator genes are functionally important gain-of-function mutations in model systems.
The estrogen receptor (ER) has been a useful therapeutic target for the treatment of breast cancer patients since the 1980s. Approximately 70% of breast cancers express ER, making these cases of cancer cells responsive to the presence of estrogen. An established treatment for ER positive (ER+) breast cancers is treatment with aromatase inhibitors, which inhibit tumor cell growth by reducing estrogen levels. Because ER is such an important factor in the growth of breast cancer cells, there has been an intensive, but unproductive, search for the gene that encodes ER, known as ESR1.
Dr. Press's team has preliminarily shown that other genes, known as ER coactivators, may affect the growth of some breast cancers. In their preliminary investigations, the researchers found mutations in the genetic sequence of some of the coactivators of ER. These observations suggest a potential effect on responsiveness to anti-estrogen therapy. The goals of Dr. Press's current investigation are as follows: 1) to confirm that ER coactivator genes are indeed altered, either amplified or mutated, in human breast cancers; 2) to determine if these ER alterations in cancers are more (or less) responsive to anti-estrogen therapy; and 3) to use human breast cancer cell lines to model response to endocrine therapy in cancers with and without ER coactivator gene amplification. If breast cancers with ER coactivator gene alterations were particularly responsive (or unresponsive) to hormonal treatments, this could substantially alter the need for these women to be treated with chemotherapy.
Mid-year Progress: Dr. Press's team continues their work on confirming that ER coactivator genes are altered, either amplified or mutated, in human breast cancers. They are using human breast cancer cell lines to model response to endocrine therapy in cancers with and without ER coactivator gene amplification to determine if these ER alterations in cancers are more (or less) responsive to anti-estrogen therapy. During the current year of funding, Dr. Press's team has identified genetic alterations in selected estrogen receptor coactivator/corepressor genes among 115 patients at their institution and among 576 breast cancers with DNA sequence data publicly available online.
The identified genetic alterations include both changes in gene copy number (gene amplification) and in genetic sequence. These analyses demonstrated mutations in nine ER co-regulator genes in breast cancers. Dr. Press's group has also evaluated genes that are co-amplified with the human epidermal growth factor receptor type 2 (HER2) gene, a type of breast cancer known to be resistant to anti-estrogen therapy. Two of the HER2 co-amplified genes appear to be promising candidates, both in terms of their functional activity in estrogen metabolism and because of the strong association with HER2 gene amplification. In the laboratory, Dr. Press and colleagues have evaluated the functional significance of both the acquired somatic mutations in ER coactivator genes and the two HER2 co-amplified genes in estrogen response pathways.
Dr. Press is recognized for his work in characterizing molecular genetic alterations of breast cancer. He also has been active in evaluating different methods used to identify genetic alterations in human cancers. He is a board-certified anatomic pathologist and has authored over 92 papers. He is currently serving as a Surgical Pathologist at the Women's and Children's Hospital, Los Angeles County and the USC Medical Center (Norris Comprehensive Cancer Center) where he also is a Professor of Pathology and the Harold E. Lee Chair in Cancer Research. He was formerly an Assistant Professor of Pathology and Surgical Pathologist at the University of Chicago (1981-1987), where he received both his MD, and PhD degrees. Dr. Michael F. Press currently serves as the Director for the Breast Cancer International Research Group Central Laboratory and the Director of the Breast Cancer research Program at USC.
Dr. Press's primary research interest is in the area of genetic alterations related to breast and gynecologic cancers. He is most interested in changes in these malignancies that lead to altered expression of oncogenes, growth factors, growth factor receptors and hereditary breast cancer genes.