Steffi Oesterreich, PhD
Professor of Pharmacology and Chemical Biology
University of Pittsburgh
Director of Education, Women's Cancer Research Center
Magee Women's Research Institute
University of Pittsburgh Cancer Institute
2012-2013 BCRF Project:
Lobular cancers account for 10% to 15% of all breast cancers. Although the incidence of invasive ductal cancers (IDC) has remained relatively constant over the last two decades, there has been a significant increase in the number of invasive lobular cancers (ILC). ILC tumors grow in a long, thin mass, which makes them difficult to detect by mammography. Subsequently, when ILC is diagnosed, tumors are often larger and have more often spread to distant sites compared to IDC. In addition, surgery of ILC is often complicated due to their unique growth pattern, which makes resection and breast conservation approaches more difficult.
Endocrine therapies, or anti-estrogen cancer therapies, are often used to treat ILCs that express the estrogen receptor (also called estrogen receptor positive, ER+). However, a portion of these breast cancers does not respond to these treatments at all. Dr. Oesterreich's team hypothesized that there are unique features in ILCs that do not respond to endocrine therapies, and that these features are different from the mechanisms underlying endocrine resistance in ER+ invasive ductal cancer (IDC), and which could be clinically targeted. Their recent progress indicates that tamoxifen, which is a form of endocrine therapy, indeed functions as an agonist in ILC cells, whereas it has more pronounced antagonist activities in IDC cells. In addition, they have identified regions in the ILC genome which are amplified or lost, and identified genes for which such copy number changes were correlated with alterations in expression. Dr. Oesterreich's team is currently deciphering whether any of these genes could contribute to endocrine resistance in ILC.
Mid-year Progress: After their finding of tamoxifen resistance in an ER+ ILC cell lines, Dr. Oesterreich's team has now performed gene expression array analysis in order to identify estrogen/tamoxifen regulated genes which might contribute to endocrine resistance in ILC. These studies have identified a number of genes from the Wnt, TGF-B and FGF signaling pathways, and the researchers are currently performing additional studies to test their potential role in ILC progression. Dr. Oesterreich has also finished in silico studies using publicly available data sets in order to identify potential drivers of ILC and has isolated DNA and RNA from a large number of clinical ILC samples. They are now planning on expression analysis of 650 candidate genes in these samples, as well as subsequent biostatistical analysis to determine whether any of these genes are associated with outcome of ILC patients.
The main interest of Dr. Oesterreich's laboratory is to further our understanding of hormone action in breast cancer, with the ultimate goal of using this knowledge for improved diagnosis and endocrine treatment of breast cancer patients. Specifically, Dr. Oesterreich's group studies how the estrogen receptor (ER) functions, how its activity is regulated by co-activator and co-repressor proteins, and if and how these mechanisms are perturbed in cancer cells. Dr. Oesterreich is also interested in novel concepts of ER action, such as its role in repression of gene transcription. Finally, an important goal is the identification of genetic markers such as polymorphisms, or epigenetic changes such as DNA methylation, which might be able to predict a patients response to endocrine therapy, i.e. which can be used to "personalize medicine." All of these studies include many aspects of translational breast cancer research utilizing basic biochemistry, molecular and cell biology, cell lines, and clinical samples.