Kornelia Polyak, MD, PhD
Harvard Medical School
Research in my laboratory is dedicated to the molecular analysis of human breast cancer. Our goal is to identify differences between normal and cancerous breast tissue, determine their consequences, and use this information to improve the clinical management of breast cancer patients. We have devoted much effort to develop new technologies that allow for the comprehensive molecular profiling of cells isolated from primary human tissue samples. Using these methods we have been at the forefront of studies analyzing purified cell populations from normal and neoplastic human breast tissue at genomic scale and utilizing interdisciplinary approaches for the better understanding of clinical breast cancer.
We characterized molecular alterations that occur during breast tumor progression using SAGE (Serial Analysis of Gene Expression) for gene expression profiling, SNP (Single Nucleotide Polymorphism) arrays and array CGH (Comparative Genomic Hybridization) for genetic changes, MSDK (Methylation-Specific Digital Karyotyping) for the characterization of global DNA methylation profiles, and ChIP-Seq (Chromatin Immunoprecipitation and next generation sequencing) for the analysis of histone modification patterns. In addition to analyzing the tumor cells we also investigated all cell types that compose normal breast tissue and in situ and invasive breast carcinomas. Using these approaches we determined that gene expression and epigenetic changes occur in all cell types during breast tumor progression, whereas clonally selected genetic alterations are restricted to tumor epithelial cells. Several of the genes we identified as aberrantly methylated in breast cancer, including the SCGB3A (HIN-1) gene, are candidate diagnostic or prognostic markers. Based on our results we also proposed that the in situ to invasive breast carcinoma progression is determined by interactions among epithelial, myoepithelial, and stromal cells and that progression occurs due to the loss of normal myoepithelial cell function. These findings change the way we approach breast tumor progression, the identification of patients with high risk for progression, and can be used for designing better cancer preventative interventions.
We have also characterized cells with stem cell characteristics from normal mammary epithelium and breast carcinomas. In the normal breast, we have been investigating molecular alterations induced by factors that influence breast cancer risk including pregnancy, breast density, and hereditary mutations in breast cancer genes with the aim of better understanding these changes and exploiting them for breast cancer preventative approaches. In breast cancer, we have been analyzing mechanisms that underlie intra-tumor heterogeneity including genetic, epigenetic, and non-hereditary changes, and the clinical consequences of intra-tumor diversity with special emphasis on tumor progression and therapeutic responses. We study breast tumors as ecosystems and apply ecological and evolutionary methods to better understand the clinical implications of tumor heterogeneity.