Notch pathway in human breast cancer
We have shown that the breast cancer cell lines and primary tumors contain a self-renewing population that is highly regulated by the Notch signaling pathway suggesting that Notch signaling could offer a novel target for breast cancer stem-cells treatment.
In addition, we have demonstrated that Notch signaling is activated in a wide range of human breast cancer cell lines and in many human breast carcinomas of different pathological grade and type. We have shown the accumulation of the activated form of Notch1 in human tumor mammary epithelial cell lines and in a variety of breast cancer samples. These included progesterone receptor (PR)-positive, estrogen receptor (ER)-positive, epidermal growth factor receptor (EGFR)-expressing, ErBb2-positive tumors of various grades, demonstrating an increase of Notch signaling in all different human breast cancer types. This was accompanied by a downregulation of Numb, which antagonizes Notch (the expression of Numb was abolished in all breast cancer samples). As a consequence of our results, we conclude that the Notch1 is a proto‑oncogene involved in the aetiology of human breast cancer. In addition, they strongly indicate that Notch inhibition may provide a potent novel therapeutic tool against breast cancer.
Very recently we have demonstrated that the Notch pathway is activated very early during breast cancer formation showing that the pathway is activated in ductal carcinoma in situ (DCIS) lesions. DCIS is a pre-invasive lesion which accounts for 30% of screen‑detected breast cancer and if left untreated progresses to invasive cancer in 50‑60% of patients. Taken together, our present study, defines for the first time, a new role of the Notch signaling pathway in breast cancer progression. The connection between Notch signaling and DCIS suggests that Notch can be a target candidate for the prognosis and treatment of the disease. Our results have significance for the early prognosis of breast cancer and the activation of Notch can be used as an early prognostic marker for the disease.
More significantly, using animal models, we have shown that inhibiting Notch signaling using its antagonist Numb reverts the transformed phenotype of human mammary epithelial tumorigenic cells and inhibits tumor formation in vivo.
In conclusion, the above data strongly suggest that inhibiting Notch signaling will prevent in vivo growth of human breast tumors.