Researchers at the FIRC Institute for Molecular Oncology, Milan, and the European Institute of Oncology, Milan, have pinpointed the connection between low levels of the protein NUMB and increased risk of breast cancer.

The gene acts as an anticancer protein by binding to well known tumour suppressor p53 and a third protein HDM2, which usually degrades p53 and prevents its cancer-busting ability.

By protecting p53 in this way, NUMB is itself acting as an anti-cancer protein, the researchers have claimed.

The research, published in Nature this month, used data from 443 breast cancer patients enrolled in a surgical trial conducted at the European Institute of Oncology between March 1998 and December 1999. A range of different cells were studied in the test tube, including human breast cells.

Immunohistochemical (protein) analysis of NUMB was performed by tissue microarray. Breast tumours with the NUMB gene in less than 10% of tumour cells were scored as NUMB-negative (114 patients), whereas tumours showing more than 10% NUMB-expressing cells were scored as NUMB-positive (329 patients).
The 443 patients were followed for an average of 4.5 years.

During the follow-up period, a total of 40 new events were registered. Ten patients developed a loco-regional event, 9 developed a controlateral carcinoma, and 21 developed a distant metastasis.

It is known that in breast cancers there is frequent loss of NUMB expression. Professor Pier Paolo Di Fiore and his team showed that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance.

In breast cancers, loss of NUMB expression causes increased activity of the receptor gene NOTCH. Thus, in these cancers, a single event—loss of NUMB expression—determines activation of an oncogene (NOTCH) and lessens the effect of the p53 tumour suppressor.

“Biologically, this results in an aggressive tumour, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry” commented Professor Di Fiore.