Myles Brown, MD
Professor, Department of Medicine, Harvard Medical School
2012-2013 BCRF Project:
(made possible by generous support from The Pink Promises Award in Memory of Patricia L. Hansen)
Physician, Oncology, Brigham And Women's Hospital
Professor of Medicine, Medical Oncology
Dana-Farber Cancer Institute
A major goal of Dr. Brown's research program is the elucidation of the mechanisms by which steroid hormones and their receptors influence normal mammary physiology and play pathologic roles in breast cancer. Focusing on estrogen receptor alpha (ER), Dr. Brown's team has provided important insights into the genomic actions of estrogen. These include the first comprehensive map of ER binding sites across the breast cancer genome, which reveals the predominance of distal regulatory sites; the demonstration that FOXA1 plays a central role in determining ER function in breast cancer cells, which highlights the importance of this pioneer factor in breast cancer; and the epigenetic approaches and new bioinformatics tools to assign function to transcriptional regulatory sites. Finally, Dr. Brown's team has developed the concept of the "cistrome," the set of authentic cis-acting binding sites of a trans-acting factor on a genome-wide scale.
Dr. Brown's team has now turned their attention to the role played by androgens and androgen receptor (AR) in breast cancer. Their studies have revealed unexpected breast cancer subtype specific roles for AR. In work published last year in Cancer Cell, Dr. Brown showed that AR plays an oncogenic role in estrogen receptor negative but HER2 positive (ER-/HER2+) breast cancer, through the induction of WNT signaling and the subsequent induction of HER3. This study suggests that AR antagonists and therapies targeting both WNT and HER2/HER3 signaling would be therapeutically synergistic in this breast cancer subtype. In contrast, recent unpublished work from Dr. Brown's lab reveals a tumor suppressive role for AR in estrogen receptor positive (ER+) breast cancer. These studies suggest that AR inhibits breast cancer growth through the inhibition of ER signaling.
The clinical development of new classes of AR antagonists including potent complete antagonists and selective AR antagonists (SARM) not currently used for breast cancer has the potential to provide new options as breast cancer therapies. For these new agents to be appropriately developed for breast cancer, a detailed understanding of the complexities of AR signaling is required. Dr. Brown's goal is precisely to elucidate the mechanisms underlying the subtype selective actions of AR in breast cancer so that clinical interventions can be developed.
Mid-year Progress: The goal of this project is to determine the role played by male hormones, androgens, in breast cancer. Scientists now understand that rather than being a single disease, there are several different types of breast cancer that depend on different factors for their growth and spread. While it has been appreciated for many years that the female hormone estrogen is critical for the growth of the most common type of breast cancer that contain the receptor for estrogen, so-called ER+ breast cancer, it is only in recent years that it has been appreciated that male hormones, androgens, also play an important role in breast cancer growth. Dr. Brown has found that depending on breast cancer type, androgens can either stimulate or inhibit breast cancer growth. This project is aimed at understanding how this occurs. This is important to breast cancer patients as new classes of drugs that block the action of androgens have been recently developed for the treatment of prostate cancer. These drugs would be potentially effective in those breast cancers that depend on androgen for growth. In contrast, other new drugs that mimic the activity of androgens in the breast without unwanted masculinizing side effects could provide a new option for the treatment of the subset of breast cancers that are growth inhibited by androgens. For these new agents to be appropriately developed for breast cancer, a detailed understanding of the complexities of androgen signaling is required. Dr. Brown's goal continues to be to precisely elucidate the mechanisms underlying the subtype selective actions of androgens in breast cancer so that new therapies can be developed.