Role of Notch Signaling in Human Breast Cancer Pathogenesis
Annual summary 30 Jun 2003-29 Oct 2006
INDIAN INST OF SCIENCE BANGALORE (INDIA)
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Notch proteins are activated upon binding to ligands of the DeltaSerrate family. In previous experiments I had found that activated allele of Notch 1 cooperates with low levels of oncogenic Ras expressing HMLE cellstermed HMLER. Further investigations revealed that Notch-IC confers protection to HMLER cells againstanoikis, a form of apoptosis triggered upon anchorage-independent growth. Eventhough Notch-IC cooperates with oncogenic Ras HMLER cells to initiate tumors in vivo, they form well encapsulated, non-metastatictumors. Inhibition of Notch signaling, however, reverts the EMT phenotype of Sum1315 breast cancer cell line,as detected by increase in epithelial E-cadherin and loss of fibroblastic marker, vimentin. In order to assess whether the observed Notch-Ras cooperation in transformation of HMLE cells in vitro also holds true in vivo innaturally arising breast tumors, immunohistochemical analysis was undertaken. While in normal breast tissueactivated Notch, its downstream target Hes5, or phospho forms of Erk12 were not detected, abundant amounts of all these proteins were detected in the same areas within breast cancer tissue. This suggests that the Notch-Ras cooperation might indeed be involved in initiating breast carcinogenesis as it occurs in vivo.
- Anatomy and Physiology
- Medicine and Medical Research