Meurette O, Stylianou S, Rock R, Collu GM, Gilmore AP, Brennan K. 2009. Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Research 69:5015-5022. pubmed
Breast cancer is a serious problem for western women (and some men), and is becoming more prevalent. Although some patients can be cured, there are many for whom treatment is not possible. This is partly because the underlying causes of the disease are not well understood. The Brennan lab has been working on a cellular signalling pathway that is crucial for the normal development of mammary glands, which now turns out to be misregulated in breast cancers. This is the Notch signalling pathway.
The Notch pathway is aberrantly activated in a wide range of cancers, including breast carcinoma. It is required to maintain the tumourigenic phenotype of many breast cancers. Notch signalling contributes to cancer partly by preventing apoptosis (i.e. cell suicide) in response to many different stimuli, including altered cell-matrix interactions. However, it was not previously known how Notch activation leads to a general suppression of apoptosis.
In this paper, Notch signalling was shown to be induced by an autocrine loop that activates a signalling protein called Akt in breast epithelial cells. Activation of Akt was necessary for Notch-induced protection against apoptosis in normal breast epithelial cells.
Importantly this Notch-Akt pathway causes breast cancer cells to become resistant to DNA damage. This occurs downstream of Akt via ASK1/JNK signalling, but not via the p53-regulatory enzyme, MDM2. This means that some breast cells aren’t able to kill themselves if their DNA becomes mutated, and can therefore survive to grow and form tumours.
The discovery that Notch signalling is altered in breast cancer and the molecular description of how this contributes to the disease will have an important future impact on breast cancer treatment. Indeed, new clinical trials are currently being set up in Manchester, that will test whether Notch inhibitors can be used to treat the disease.