There is increasing evidence that the same molecular pathways regulating the self-renewal of stem cells are also being employed in cancer progression. The Notch/Numb signal transduction pathway has been implicated in the self-renewal of stem cells in hematopoietic, skin, neural, germ and breast tissue. In addition, aberrant Notch/Numb signaling has been observed in several human cancers, including acute T-cell lymphoblastic leukaemia, cervical, prostate, lung cancer and is strongly implicated in tumourigenesis. Furthermore, aberrant Notch/Numb regulation during the self-renewal of stem cells may cause certain human cancers. We are presenting evidence that Notch/Numb signaling is aberrantly activated in a wide range of breast cancer cell lines, ductal carcinoma in situ (DCIS) of the breast and invasive breast cancer using a wide range of experimental procedures including RT-PCR, Western blotting analysis, soft agar assays and immunohistochemistry. Components of the Notch signaling pathway were overexpressed in all breast cancer tissue samples and cells lines tested. Furthermore, expression of the negative regulator, Numb, was consistently downregulated in all the samples analyzed. We have also demonstrated that Notch activation is required to maintain transform phenotype of human breast cancer cells. More significantly, we show that attenuation of Notch signaling reverts the transformed phenotype of human breast cancer cell lines, and inhibits tumor formation in vivo. Based on these findings we propose that abnormal Notch signaling may contribute to mammary carcinogenesis by deregulating the self-renewal of normal mammary stem cells. Altogether our results strongly indicate that Notch signaling is increased during breast cancer progression suggesting that inhibition of Notch signaling may be a therapeutic strategy for this disease.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA