A new study unravels a molecular mechanism that explains why some forms of breast cancer are more aggressive and resistant to chemotherapy than others. The findings may soon lead to new prevention strategies and therapies.

Due to the great strides that have recently been made in the treatment and prevention of breast cancer, survival rates for this malignancy are heartening.

Almost 90% of breast cancer patients have a 5-year survival rate, according to the latest statistics, and the number of breast cancer deaths has declined in recent years.

However, the National Cancer Institute (NCI) still estimate that in 2017, 40,610 women will have died from the disease.

Factors that influence the outlook for breast cancer patients are varied and include stage, tumor grade, and hormone receptor status.

Previous research—whose first author is Ivan Nicola Colaluca, from the FIRC Institute for Molecular Oncology Foundation in Milan, Italy—revealed that the expression of a certain protein called Numb also influences how aggressive the cancer is.

Numb is crucial in the fight against tumor formation, and loss or underexpression of this protein renders breast cancer more aggressive and less responsive to chemotherapy.

In this previous research, the Italian-based researchers showed that the Numb protein works its protective "magic" by preventing the destruction of another tumor suppressor called p53.

In the new study—first authored by the same Colaluca—the team unravel, in more complex detail, the molecular mechanism by which Numb prevents the formation of aggressive breast cancer.

The findings, which were published in the Journal of Cell Biology, pave the way for new and more effective therapies that could improve the outlook for breast cancer patients.

Pier Paolo Di Fiore, of the FIRC Institute for Molecular Oncology, co-led the study together with Salvatore Pece and Marina Mapelli, of the European Institute of Oncology, also in Milan, Italy.

Untangling a complex molecular interaction

The senior authors explained their findings, saying, "There is a protein in our cells, called p53 that protects from tumors. When cells lose p53, they become malignant."

"Another protein, called Mdm2, can destroy p53. Finally, a third protein called Numb blocks Mdm2 and prevents it from destroying p53. In essence, when there is enough Numb around, the levels of p53 are high and cells are protected," explained the researchers.

"If, for whatever reason," the authors continued, "Numb decreases then also p53 decreases and the cells become malignant."

"In the study, we uncovered the molecular mechanism through which Numb blocks Mdm2 (and therefore allows p53 to stay high)," said DiFiore and his colleagues.

But the researchers' discovery is even more complex. To understand this complexity, we need to bear in mind that, "In the cell, Numb is produced in four slightly different variants (what we technically call isoforms). Only two of the isoforms, -1 and -2, can block Mdm2. "

Investigating the effects of these isoforms in breast cancer, the researchers found that "in a certain number of tumors the Numb isoforms-1 and -2 were very low (and therefore p53 [was] low)."

In fact, when comparing tumor cells from various breast cancer patients, DiFiore and his team found that the cells with low Numb-1 and Numb-2 were more resistant to cisplatin, a common chemotherapy drug.

Additionally, when the researchers treated these cancer cells with an Mdm2 inhibitor, the levels of tumor-suppressing p53 surged, which made the cells more vulnerable to the chemotherapy drug.

So, the team "reasoned that breast cancers displaying reduced levels of Numb-1 and -2, being resistant to genotoxic agents, might also display poorer disease outcome," explains Pece.

Therefore, the researchers carefully examined data on 890 people with breast cancer and found a strong association between low levels of the isoforms Numb-1 and -2 and the risk of aggressive breast cancer.

"Those breast tumors with low -1 and -2 are more aggressive, they metastasize more easily, and are also more resistant to chemotherapy."

Paving the way for new drugs

There are important clinical implications of these findings, the authors said. One such implication would be the development of drugs that recreate the effect of Numb on Mdm2. In the near future, DiFiore and his team plan to develop such drugs.

"This is not an easy task," said the senior researchers. "However, some of the propaedeutic steps to achieve this goal were performed in our study, by identifying the 'piece' of Numb on which these hypothetical drugs could be modeled."

"Another possibility," they continued, "would be to exploit already existing efforts to develop drugs that can block Mdm2."

More immediately, however, the scientists plan to apply themselves to figuring out the reason why Numb-1 and -2 are low in breast cancer.

—Ana Sandoiu