Researchers from Harvard Medical School (HMS) have discovered that dual genetic signals are required to disrupt the framework of normal breast tissue during early tumor development. While most genes associated with breast cancer can only deliver one of those signals, one common breast cancer gene, HER2 (also called ErbB2), is able to provide both culprit signals.
This discovery that breast tissue needs to be told to proliferate and also must be told to avoid programmed cell death (apoptosis), was made using a laboratory-derived 3-D cellular model that allows cultured breast cells to behave like their counterparts in normal breast glands. It is reported in the Oct. 4 issue of Cell. Joan Brugge, HMS professor of cell biology, in whose laboratory the research was performed, believes this new information reveals important insights into mechanisms associated with cancer development that could be helpful in identifying targets for future anti-cancer therapy.
The normal breast is composed of clusters of spherical structures with hollow centers where milk is secreted. In the model used by the Brugge laboratory, these hollow spaces are formed as normal cells in the center die. Furthermore, the hollow space is maintained by an inherent surveillance system that induces death, or apoptosis, of excess proliferating cells.
To simulate how cancer leads to the loss of hollow spaces in breast tissue, lead author Jayanta Debnath, a postdoctoral fellow in Brugge’s laboratory and a clinical fellow at Brigham and Women’s Hospital, and colleagues introduced the HER2 or cyclin D1 gene into cultured breast cells and followed their effects in the 3-D model. Both HER2 and cyclin D1 stimulated proliferation of the breast cells into the hollow spaces; however, the cyclin D-producing tissues retained hollow areas because the proliferating cells succumbed to death by apoptosis.
In contrast, HER2 provided a survival (or anti-death) signal, which allowed the cells to fill the hollow space. These filled structures resemble the pathology of early breast tumors. Thus, these studies indicate that during the early development of breast cancer, tumor cells must not only proliferate, but also overcome the normal cell death mechanisms that maintain the glandular architecture.