CEACAM1 and SASH1 regulate NOTCH1 Signaling in a model of breast cell lumen formation via the novel protein DLK1.

摘要

Breast cancer, originating from malignant transformation of luminal mammary ducts, affects millions of women worldwide. Research aimed at understanding breast cancer focuses on either pathways or genes that are deregulated during malignant transformation. In the case of newly absent tumor suppressor genes, their reintroduction may restore normal functions such as lumen formation. A reversion of breast tumors requires research into the mechanisms contributing to the down regulation of tumor suppressors and the genes that, in turn, are regulated by them.;In this regard, CEACAM1, a gene highly expressed in normal mammary glands, is frequently downregulated in breast cancer. Previous studies focused on CEACAM1 have shown that when CEACAM1 is transfected into the breast cancer cell line MCF7, that exhibits undetectable levels of CEACAM1 and is unable to form acini, lumen formation is restored. Gene chip analysis on MCF7 cells transfected with CEACAM1 reveals that the adaptor protein SASH1 is upregulated during restored lumen formation. We have found that SASH1, previously identified as a tumor suppressor in breast cancer, regulates lumen formation through the modification of other genes such as DLK1/2 that regulates the Notch signaling pathway, a major program controlling glandular development. Since normal mammary development requires the coordination of apoptotic, differentiation, migration and cell adhesion pathways all of which are regulated by CEACAM1, SASH1, DLK1/2 and NOTCH we can propose a method of lumen formation initiated by CEACAM1 that when silenced leads to a possible mechanism of breast tumor development.