Investigators have found two ways in which Notch contributes to the formation of breast tissue. Additionally, they deduced how the inappropriate expression of the Notch pathway may contribute to breast cancer.
The researchers discovered that the Notch protein controls breast stem cell number during development and instructs stem cells to produce luminal cells. They observed that Notch restricts breast stem cell number. When Notch is switched off, there was an expansion in breast stem cells.
The team also noted that Notch is important for ensuring that stem cells produce the sleeve of cells that normally line breast ducts. These luminal cells may be the cells that give rise to breast cancer, according to the scientists.
This discovery builds on the team’s 2006 identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations, which enhanced the prospect of investigating the genetic control of their lineage specification and differentiation.
Scientists explored the role of the Notch pathway within the mammary epithelial hierarchy by showing that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion.
Conversely, Notch was found to be preferentially activated in the ductal luminal epithelium in vivo and promoted commitment of MaSCs exclusively along the luminal lineage.
The Notch signaling targeted luminal progenitor cells for expansion, which led to hyperplasia and tumorigenesis, the researchers report. The work spotlights the potential importance of deregulated Notch in ductal precursor cells as a forerunner to breast cancer, according to the team.
They caution, however, that it is too early to tell whether the design of anti-Notch therapies could help patients facing breast cancer.
The findings, compiled by scientists at The Walter and Eliza Hall Institute of Medical Research and the Department of Medical Oncology at the Royal Melbourne Hospital, were published in the Oct. 8 issue of Cell Stem Cell.