Over-expression of Notch receptors and aberrant Notch signaling have been reported in both preinvasive ductal carcinoma in situ and invasive breast cancer. The Notch 4 receptor, in particular, is preferentially activated in human breast cancer stem cell-enriched populations, and inhibition of Notch 4 reduces tumor formation of human breast cancer cells in xenograft models (Harrison, 2010). Myc gene amplification has also been found in about 15% of breast tumors, and 22%–35% of tumors exhibit overexpression of Myc at the transcriptional level. Transgenic mice over-expressing MYC develop invasive adenocarcinomas and preferentially harbor secondary activating mutations in KRas. We examined whether Notch receptors were activated in mouse mammary tumors over-expressing MYC and activated KRAS (KRASV12) and found Notch 4 to be significantly activated in these tumors compared to normal mammary tissue. Furthermore, Notch 4 was localized to the nucleus in the tumors over-expressing MYC and KRASV12, but not in mammary glands over-expressing MYC or activated KRASV12 alone. To examine the requirement of Notch4 in mammary tumorigenesis by MYC and KRASV12, we transplanted mammary epithelial cells isolated from Notch4 knockout mice and wild-type mice that have been transduced with MYC and KRASV12 into the mammary glands of syngeneic mice. There was a significant reduction in the onset of tumorigenesis in mammary glands that had been transplanted with mammary epithelial cells lacking Notch4. These findings suggest that Notch4 is important in mammary tumorigenesis induced by cooperation of MYC and activated RAS. We are currently examining the relevance of Nocth4 activation in human breast cancers that over-express MYC and the mechanism by which Notch4 promotes tumorigenesis by Myc and activated RAS.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-01.

2012