Michael F. Press, MD, PhD

2009-2010 BCRF Project:
(made possible by generous support from Teleflora)

Estrogen receptor protein in breast cancer cell nuclei has been a useful therapeutic target for treatment of breast cancer patients since the 1980s. Estrogen receptor in tumor cell nuclei facilitates responsiveness to circulating estrogen hormones in both normal tissues and in breast cancer cells. Approximately 70% of breast cancers have ER protein expressed and these cancers respond to estrogens with stimulation of tumor cell division. An established treatment for ERpositive breast cancers is treatment with hormone-like inhibitors of ER action to inhibit tumor cell growth. Because ER is such an important growth regulator of breast cancer cells there has been a largely unproductive search for mutations in the gene that encodes ER, known as ESR1.

Last year a European group reported the observation that ESR1 gene is amplified in approximately 20% of human breast cancers. The Press laboratory, and others, have shown that ESR1 is only infrequently amplified (<1%). Gene amplification is a type of genetic alteration in which a region of a chromosome containing one or more genes is duplicated, usually in tandem, many times over so the genes in this region of the chromosome are represented not by a single copy of the gene on that chromosome but by many copies of the gene. This duplication or amplification of a gene would facilitate the production of large quantities of the protein encoded by this gene. Although they did not find amplification of ESR1, Dr. Press and team have preliminarily shown that other genes, known as ER coactivators, may be amplified in some breast cancers.

This observation has important implications for women who have breast cancer. It suggests that ER coactivators may be present at high levels in some cancers facilitating responses to estrogen stimulation. This also suggests a potential effect on response to anti-estrogen therapy. The goals of this investigation are 1) To confirm that ER coactivator genes are indeed amplified in human breast cancers, 2) To determine if these 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 amplification 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 Report:
Approximately 70% of breast cancers have ER protein expressed and these cancers respond to estrogens with stimulation of tumor cell growth. An established treatment for ER-positive breast cancers is treatment with hormone-like inhibitors of ER action to inhibit estrogen-stimulated tumor cell growth. While this therapy is initially successful in the majority of women, a substantial number of women have breast cancers that are resistant to these anti-estrogen therapies either from the beginning of treatment (de novo resistance) or subsequently become resistant (acquired resistance). Estrogen receptor (ER) protein requires a large number of other interacting proteins to successfully stimulate gene expression in tumor cells, and Dr. Press believes some of the genes encoding these proteins in cancer cells carry either inherited DNA sequence alterations (single nucleotide polymorphisms) or acquired DNA sequence alterations (somatic mutations including gene amplification) that influence ability of ER to stimulate cell growth and/or the ability of anti-estrogen therapy to interfere with this stimulation.

In order to address this issue he and his colleagues have the following research aims: 1. Determine which, if any, estrogen receptor co-regulators, have gene copy number aberrations consistent with gene amplification; 2. Assess the status of conventional predictive markers (ER, PR, HER2) and ER phosphorylation status for comparison with genetic alterations identified in a "pilot set" and "validation set" of breast cancer cases. Their initial research confirms that there are DNA sequence alterations, including increased gene copy number or gene amplification, in several ER co-activator genes. The researchers are currently comparing the association of these alterations with conventional biomarkers of breast cancer outcome (ER, PR and HER2) and with clinical outcome. They will assess whether these alterations are associated with a lack of responsiveness to anti-estrogen therapy such as tamoxifen.

Bio:
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' 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.