Study Suggests How the BRCA1 Protein May Help Suppress Tumors ► NCI Cancer Bulletin for September 20, 2011 - National Cancer Institute

NCI Cancer Bulletin for September 20, 2011 - National Cancer Institute: Study Suggests How the BRCA1 Protein May Help Suppress Tumors

Mutations in the BRCA1 gene are known to increase a woman’s lifetime risk of developing breast and ovarian cancers, but researchers are still investigating how the protein encoded by this gene helps suppress the formation of tumors. A study by Dr. Inder Verma and his colleagues at the Salk Institute for Biological Studies in the September 8 Nature offers some clues.

Using mice and human breast cancer cells, the researchers identified a series of abnormalities in cells lacking the BRCA1 protein. Taken together, the findings suggest that BRCA1 helps to preserve the integrity of a cell’s genome by “silencing” stretches of repetitive DNA that might harm the cell if “awakened,” or transcribed.

When BRCA1 is missing, the researchers found, certain chromosome regions are no longer maintained in a condensed state. Normally, these regions (known as constitutive heterochromatin) are bound tightly; as a result, certain stretches of repetitive DNA are silent. In the absence of BRCA1, however, cells may produce relatively large amounts of RNA from the repetitive regions.

This activity, in turn, may make the genome less stable and set the stage for cancer. “When cells make a lot of this noncoding RNA, it can lead to DNA damage,” said co-author Dr. Quan Zhu. “This kind of damage is thought to cause cancer.”

The maintenance of distinct chromosomal regions in a condensed state may underlie the tumor-suppressive effect of the protein, wrote Dr. Ashok Venkitaraman of the Hutchison/Medical Research Council Research Centre, Cambridge, UK, in an accompanying editorial. The finding, he added, “might herald a breakthrough” for the field.

Over the past decade and a half, many studies have proposed potential functions for the normal BRCA1 protein, such as repairing damaged DNA or helping with transcription. Dr. Verma and his colleagues believe their findings could provide a framework for understanding the role this protein plays in a number of cellular functions.

By and large, the researchers note, their observations in mice and in human cells are consistent with previous studies of BRCA1. “We observed all of the cellular problems that people have reported over the years related to the loss of BRCA1,” said co-author Dr. Gerald Pao.

The activation of repetitive DNA observed in this study was seen in mouse and human tumors. “Whether, and how, this event promotes cancer development in carriers of germline BRCA1 mutations is not yet evident,” Dr. Venkitaraman wrote. Nonetheless, the study “reveals an intriguing new pathway for tumor suppression,” he added.

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