AACR Outstanding Investigator Award for Breast Cancer Research, funded by Susan G. Komen for the Cure®

SPOTLIGHT

2009 Award Recipient

Chapel Hill, NC

Dr. Perou's synthesis of biology, informatics, and molecular genetics informs his breast cancer research from the lab to the clinic and into the population.

His cutting edge, innovative work continues to make far-reaching impacts on many aspects breast cancer research. Dr. Perou's publications in Nature, the New England Journal of Medicine, and PNAS, among other high impact journals, have been discussed and praised in numerous editorials and his scientific discoveries are being incorporated in clinical practice worldwide. He is a superb teacher and has delivered plenary addresses at meetings of virtually every important society from basic research to clinical care. In essence, Dr. Perou's groundbreaking work in molecular profiling defined a new field and is changing both clinical practice and our understanding of the epidemiology of breast cancer.

Dr. Perou's research on breast cancer began at Stanford University. He joined Drs. David Botstein and Pat Brown when their lab was conceptualizing the use of cDNA expression microarray technology. Dr. Perou initiated the human cancer genetics program working side-by-side with other postdoctoral fellows as the team was literally building machines and computational tools with which to perform microarray expression analysis. The outcome of Dr. Perou's efforts was a molecular profile of breast cancer tumors published on the cover of Nature in August of 2000. In 2001, Dr. Perou joined the faculty of UNC-Chapel Hill. He now leads an interdisciplinary team of biologists, geneticists, bioinformaticists, clinicians, and epidemiologists focused on characterizing the diversity of human tumors using DNA microarrays, molecular genetics, and cell biology to classify tumors into subtypes of clinical importance. This work represents one of the most important findings in breast cancer and health disparities in the last decade.

Dr. Perou and colleagues have demonstrated that breast tumors can be classified into five molecular subtypes with clinical implications. These included two ER+ subtypes, Luminal A and B, a normal-like subtype, and two ER-negative subtypes, HER2-enriched and Basal-like. The Basal-like subtype was a new, molecularly defined type of breast cancer - a cancer subtype arising from the duct's basal, not luminal, cell. Not only is the basal-like subtype as common as the HER2 amplified subtype, but the basal-like breast cancer classification has prognostic significance. Women with the basal cell gene expression profile have a poor prognosis with standard therapy. Unlike ER+ tumors and HER2+ tumors, there is currently no targeted therapy for basal-like tumors.

Dr. Perou and others have begun delving into the pathways extant and responsible for this tumor subtype including the epidermal growth factor receptor (EGFR) pathway and BRCA1. His work has helped us understand the etiology of these subtypes, explain resistance to chemotherapy, and conceptualize new therapies targeted to different subtypes. His research will change our approach to treating women with breast cancer and have a significant impact morbidity and mortality.

Dr. Perou and his colleagues, particularly Bob Millikan and Lisa Carey, have also translated the molecular subtypes to the population. Using newly-diagnosed cases from a large population-based study, they discovered that compared to pre-menopausal Caucasian women, pre-menopausal African American women are diagnosed with the Basal-like tumors twice as often. This difference has real implications for breast cancer research of racial/ethnic disparities in breast cancer mortality.

Dr. Perou's work holds the promise of novel prevention strategies: risk factors are not the same for all breast cancers. Using the Carolina Breast Cancer Study (CBCS), Drs. Millikan and Perou showed that pregnancy was protective for Luminal A tumors; that is, increased parity and younger age at first full-term pregnancy each were associated with reduced risk.

Surprisingly, increased parity and younger age at first full-term pregnancy were associated with increased risk of basal-like breast cancer. This joins other reports suggesting that subtypes display etiologic heterogeneity with distinct risk factors for each subtype.

More recently, Dr. Perou and colleagues showed that DCIS lesions display phenotypes analogous to the subtypes of invasive breast carcinomas. This was substantiated in his collaboration with Dan Medina and Craig Allred that used gene expression profiling of DCIS lesions. Interestingly, Basal-like DCIS was associated with unfavorable prognostic variables including high-grade nuclei, overexpression of p53 (indicative of p53 mutation), and a high Ki-67 labeling index. These studies show that potential precursor lesions may give rise to specific breast cancer subtypes. A molecular classification of DCIS may have important therapeutic implications.

Dr. Perou has launched an exhaustive study to molecularly profile extant genetically engineered mouse models of breast cancer and, through his team's novel bioinformatics analysis, compare the mouse breast cancer phenotypes with those of humans. They are already launching combination chemo and biologic therapy trials in relevant mouse models, surely a harbinger of how future human trials will be devised through sophisticated preclinical studies. Dr. Perou has assembled both local and national teams with talent ranging from molecular geneticists to statisticians to expert clinicians. He is a magnet for student post-docs and faculty wishing to modernize their approaches.

Dr. Perou has published over 100 papers since 1999 in top-tier journals such as the New England Journal of Medicine, Journal of the American Medical Association, Cancer Cell, and Genome Biology. The impact and quality of these publications represent remarkable progress, and as a result, Dr. Perou enjoys international recognition in his field.