Joan S. Brugge, PhD

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.