09:24pm Saturday 18 January 2020

Breast cancer: Microproteins essential for cancer growth

Breast cancer is one of the leading causes of death in women worldwide. In order to develop new therapies, it is necessary to understand exactly how breast cancer cells function. Scientists at the German Cancer Research Center have taken an important step in this direction: In tumor tissue from breast cancer patients, they discovered a tiny protein that is essential for the growth of the tumor cells. If the gene for the microprotein is switched off, the growth of the breast cancer cells is inhibited.

The breast cancer cell line MCF7 produces the microprotein CASIMO1 (green). Shown in red is the cytoskeleton protein actin, the cell nuclei appear blue. © M. Polycarpou-Schwarz; S. Diederichs, DKFZ

In women, breast cancer is the most common cancer. One in eight women suffers from a malignant tumor in her breast during her life. The type of breast cancer is crucial for prognosis and therapy. Depending on certain receptors on the surface of the cancer cells, the tumors are divided into two groups: hormone receptor positive and hormone receptor negative breast cancer. Most tumors of the breast are hormone receptor-positive, the cancer cells carry on their surface receptors for the sex hormones estrogen and progesterone.

“Although the group of hormone receptor-positive tumors has a better prognosis than other breast cancers, they are responsible for many deaths simply because of their frequency,” explains Sven Diederichs of the German Cancer Research Center. “To find new ways to treat breast cancer, we first need to understand exactly how the tumor cells work. So far, our knowledge about the development and progression of the disease is not enough to treat it optimally, “he emphasizes.

Diederichs and his team compared breast cancer cells with breast tissue cells of healthy women. They found that a particular microprotein was much more common in breast cancer cells than in normal cells.

Microproteins have not been known for a long time. To produce a microprotein, the cell reads genetic material that has long been thought to contain no protein instructions. “Molecular biology databases are teeming with these supposedly noncoding RNA molecules, which are sometimes used by the cells to produce small proteins,” Diederichs says.

In recent years, microproteins have been found to play a role in muscle development and cardiovascular disease. The microprotein CASIMO1, which was discovered by the DKFZ researchers and consists of just 83 amino acids, is the first to show any function in cancer.

CASIMO1 is present in breast cancer cells, especially of hormone receptor-positive tumors, in high concentration. The underlying gene is used extensively for protein production. In experiments on cell cultures, the scientists around Diederichs switched off the CASIMO1 gene. This demonstrated the importance of CASIMO1 for the survival of breast cancer cells: The lack of the microprotein interrupted the cell cycle of the breast cancer cells and thus inhibited their growth.

Next, the DKFZ scientists want to examine other microproteins that they have already found in patients with breast cancer or lung cancer. “The long-term hope is to be able to use these small proteins as therapeutic targets and to inhibit them with drugs,” says Diederichs.

Maria Polycarpou-Schwarz, Matthias Groß, Pieter Mestdagh, Johanna Schott, Stefanie E. Grund, Catherina Hildenbrand, Joachim Rom, Sebastian Aulmann, Hans-Peter Sinn, Jo Vandesompele, Sven Diederichs. The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. Oncogene (2018), DOI: 10.1038/s41388-018-0281-5

A picture is available for download:

Picture Caption: The breast cancer cell line MCF7 produces the microprotein CASIMO1 (green). Shown in red is the cytoskeleton protein actin, the cell nuclei appear blue.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.





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