Researchers map molecular interaction that prevents aggressive breast cancer

December 21, 2017, Rockefeller University Press
An x-ray crystallographic structure of the Numb domain that binds to Mdm2, with the crucial stretch of 11 amino acids--only present in Numb isoforms 1 and 2--shown in red. Credit: Colaluca et al., 2018

Researchers in Italy have discovered how specific versions of a protein called Numb protect the key tumor suppressor p53 from destruction. The study, which will be published December 21 in the Journal of Cell Biology, suggests that the loss of these particular Numb proteins makes breast cancers more aggressive and resistant to chemotherapy, but points the way toward new therapeutic approaches that could improve patient outcome by preserving p53 levels.

Cells produce several alternative isoforms of Numb by differentially processing, or splicing, the mRNA encoding Numb to include or exclude specific regions of the protein. How this alternative splicing affects Numb's various functions remains unclear.

In mammary gland stem cells, for example, Numb binds and inhibits an enzyme called Mdm2, preventing it from targeting p53 for degradation. Numb therefore stabilizes p53 and allows this tumor suppressor protein to limit stem cell proliferation. If the stem cells lose Numb, however, p53 levels plunge and the cells proliferate uncontrollably, leading to the emergence of cancer that drive the growth of breast tumors. Cancer cells that lack p53 are also more resistant to chemotherapy drugs that kill cells by damaging their DNA.

A team of researchers based in Milan set out to identify how Numb binds to Mdm2. The team was led by Pier Paolo Di Fiore of the FIRC Institute for Molecular Oncology (IFOM), the European Institute of Oncology (EIO), and The University of Milan, as well as Salvatore Pece of EIO and The University of Milan and Marina Mapelli of EIO.

The researchers found that a small region of Numb—comprising just 11 amino acids—is responsible for binding and inhibiting Mdm2. This region is present in Numb isoforms 1 and 2 but excluded from isoforms 3 and 4. Accordingly, depleting Numb-1 and -2 from reduced the levels of p53, whereas depleting Numb-3 and -4 had no effect.

The researchers then compared tumor cells isolated from multiple different breast cancer patients and found that cells expressing lower amounts of Numb-1 and -2 were more resistant to the chemotherapy agent cisplatin. Treating these cells with an Mdm2 inhibitor boosted p53 levels and increased the ' sensitivity to cisplatin.

"We 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.

The team therefore analyzed the case history of 890 and found that low Numb-1 and -2 levels correlated with an increased risk of aggressive, metastatic disease, particularly for the luminal subtype of breast cancers, which tend to retain a normal, functional copy of the .

"Our results show how Numb splicing specifically impacts the regulation of p53 and prognosis," Mapelli says.

"We hope that it will be possible to exploit the knowledge of the molecular basis of the Numb-Mdm2 interaction in the rational design of molecules that can mimic the crucial region in Numb and inhibit Mdm2 to relieve p53 dysfunction in Numb-defective breast cancers," Di Fiore says.

Explore further: Researchers explore a potential therapeutic approach against cancer stem cells

More information: Colaluca et al., Journal of Cell Biology (2018). DOI: 10.1083/jcb.201709092

Related Stories

Researchers explore a potential therapeutic approach against cancer stem cells

March 15, 2017
Many cancer patients that receive chemotherapy go into remission at first, but relapse after treatment is discontinued. There is increasing evidence that this is due to the presence of cancer stem cells—cells that reproduce ...

Research identifies a way to make cancer cells more responsive to chemotherapy

May 23, 2013
Breast cancer characterized as "triple negative" carries a poor prognosis, with limited treatment options. In some cases, chemotherapy doesn't kill the cancer cells the way it's supposed to. New research from Western University ...

PUMA pathway is a weak link in breast cancer metastasis

December 11, 2017
Substantial advancements have improved the success of chemotherapy, radiation, and surgical treatments for primary breast cancers. However, breast cancer that has spread, or metastasized, to other parts of the body remains ...

Novel therapeutic target discovered for estrogen receptor positive (ER+) breast cancer

November 17, 2017
Researchers at the Icahn School of Medicine at Mount Sinai have identified a protein that can be targeted to suppress growth of a common type of breast cancer known as "estrogen receptor positive" (ER+), including ER+ cancers ...

Genetic targets to chemo-resistant breast cancer identified

October 3, 2017
Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Recommended for you

Targeting molecules called miR-200s and ADAR2 could prevent tumor metastasis in patients with colorectal cancer

April 24, 2018
Colorectal cancer is the third most common cancer worldwide and the third-leading cause of cancer-related deaths. The main cause of death in patients with colorectal cancer is liver metastasis, with nearly 70% of patients ...

Changes in breast tissue increase cancer risk for older women

April 24, 2018
Researchers in Norway, Switzerland, and the United States have identified age-related differences in breast tissue that contribute to older women's increased risk of developing breast cancer. The findings, published April ...

Removing the enablers: Reducing number of tumor-supporting cells to fight neuroblastoma

April 24, 2018
Investigators at the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles provide preclinical evidence that the presence of tumor-associated macrophages—a type of immune cell—can negatively ...

Technology used to map Mars now measuring effect of treatment on tumours

April 24, 2018
A machine learning approach for assessing images of the craters and dunes of Mars, which was developed at The University of Manchester, has now been adapted to help scientists measure the effects of treatments on tumours.

New test could tell doctors whether patients will respond to chemotherapy

April 24, 2018
Less than half the patients diagnosed with cancer respond favorably to chemotherapy, but a new method for testing how patients will respond to various drugs could pave the way for more personalized treatment.

Vitamin A derivative selectively kills liver cancer stem cells

April 23, 2018
Acyclic retinoid, an artificial compound derived from vitamin A, has been found to prevent the recurrence of hepatocellular carcinoma (HCC), the most common form of liver cancer. Now, in research published in Proceedings ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.