Titles and Affiliations
Louise Foote Pfeiffer Professor of Cell Biology
Director, Ludwig Center at Harvard
Member, BCRF Scientific Advisory Board
Research area
Using laboratory models to determine the origins of estrogen receptor-positive breast tumors.
Impact
In estrogen receptor (ER)-positive breast cancer, the most common form of breast cancer, estrogen signals through this receptor to drive tumor growth. In contrast, in non-cancerous breast tissue, breast cells can be ER-positive, but they do not grow in response to estrogen. The ‘switch’ that occurs that makes ER-positive breast cells proliferate in response to estrogen has not been identified. Understanding how this switch happens could shed light on how ER-positive breast cancer is initiated and, ultimately, how to prevent it.
Progress Thus Far
Until recently, studying the evolution of ER-positive breast cells and how they become malignant cancer cells has been limited because ER-positive breast cells are difficult to grow in laboratory cell cultures. Dr. Brugge and her team successfully developed breast ‘mini-organs’, termed organoids, to allow for the growth of ER-positive breast cells in the lab and study of their proliferation in response to estrogen. Using these organoids, they can investigate the mechanisms associated with ER-positive breast cancer initiation. The team has optimized the organoids and can now grow ER-positive breast cells that behave similarly to how these cells would respond in breast tissue.
In collaboration with BCRF investigator Samuel Aparicio, Dr. Brugge and her team identified cells with genetic changes in normal breast tissue that display properties suggesting that they are the cells of origin of ER-positive breast cancer. The team sequenced the genes in more than 48,000 individual breast cells isolated from 28 women without breast cancer, including 19 individuals with inherited BRCA1 and BRCA2 gene mutations, which are known to significantly increase breast cancer risk. By studying samples from healthy women, the team hoped to pinpoint the genetic changes that might make up the earliest steps in tumor formation. They found genetic alterations that occur over a person’s lifetime and that are relatively rare and harmless on their own but can accumulate and potentially lead to cancer. The team consistently found cancer-like mutations across almost all individuals—many of which are frequently observed in breast cancers—suggesting they play a role in how normal cells become cancer cells.
What’s next
Dr. Brugge will continue experiments designed to establish whether rare ER-positive proliferative cells exist in normal breast tissues and determine whether any of the common genetic alterations associated with breast cancer, including candidate genes in the observed early genetic alterations, are able to convert ER-positive cells to a state where they proliferate in response to estrogen.
Biography
Dr. Brugge is Co-Director of the Ludwig Center at Harvard Medical School. A graduate of Northwestern University, she did graduate work at the Baylor College of Medicine, completing her PhD in 1975, followed by postdoctoral training at the University of Colorado with Dr. Raymond Erikson. Dr. Brugge has held full professorships at the State University of New York, Stony Brook, and the University of Pennsylvania, where she was also named an investigator at the Howard Hughes Medical Institute. From 1992-1997 Dr. Brugge was Scientific Director of the biotechnology company ARIAD. She joined Harvard in 1997 as Professor of Cell Biology, was Chair of Cell Biology from 2004 – 2014, and became Co-Director of the Ludwig Center at Harvard in 2014.
Dr. Brugge’s awards include an NIH Merit Award, an American Cancer Society Research Professorship and the Senior Career Recognition Award from the American Society of Cell Biology. She is the recipient of BCRF’s 2015 Jill Rose Award for research excellence. She has been elected to the American Academy of Arts and Sciences, the National Academy of Sciences and the Institute of Medicine.
Dr. Brugge is investigating the mechanisms involved in breast cancer initiation and progression. Her laboratory has utilized three dimensional cultures of normal breast cells and breast tumor cells to recapitulate the organization of cells in their natural context and provide important insights relating to the mechanisms whereby genes that are altered in breast cancer contribute to tumor formation and progression as well as those that mediate resistance to cancer therapies.
