Elucidating the Tumor Suppressive Role of SLITs in Maintaining the Basal Cell Niche
Abstract
The research performed over the last twelve months is based on the hypothesis that SLIT/ROBO1 signaling regulates interactions between myoepithelial and luminal epithelial cells, and that loss of this activity results in the destabilization of the basal cell niche. We analyzed the Slit2-/-;Slit3-/- and Robo1-/- null mammary gland phenotypes using a battery of immunohistochemical markers and identified discohesive, hyperplastic lesions with basal characteristics. Adhesive contacts between cells appear largely normal. The lesions have a basal character in that they contain excess basal cells, but they are not triple negative (ER?, PR?, HER2?). We performed serial transplantation of knockout tissue and discovered that the Slit2-/-;Slit3-/- tissue displays a longevity phenotype. Mammosphere assays revealed significantly more CK8- positive cells in Slit2-/-;Slit3-/- tissue. These data suggest that loss of Slit2 and Slit3 spares cell divisions along the luminal lineage, allowing the outgrowth of luminal-enriched, lateral bud structures that persist for 5-10 additional generations. Thus disruption of this basal niche, by knocking out Slit2 and Slit3, results in hyperplastic lesions and deregulation of stem/ progenitor cell populations. Our research promises to provide insight into the mechanisms by which normal stem/progenitor cells are regulated, leading to potential insights into how they may be deregulated upon cancerous transformation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2009
- Accession Number
- ADA515794
Entities
People
- Lindsay Hinck
Organizations
- University of California, Santa Cruz