A long-noncoding RNA regulates repair of DNA breaks in triple-negative breast cancer cells

A long-noncoding RNA regulates repair of DNA breaks in triple-negative breast cancer cells

 

A BRCA1 mutation is associated with a higher risk for triple-negative breast cancer (TNBC), which represents about 10 to 20 percent of all breast cancer cases. TNBC test negative for both the estrogen and progesterone receptors and the cell surface receptor Her2, hence its name. Since hormones are not supporting growth, the cancer is unlikely to respond to hormonal therapies and medications that target HER2.

Because of these limited therapeutic targets, many cancers, including TNBCs, are typically treated with surgery and a combination of radiation and chemotherapy that induce various types of DNA damage. However, many TNBC patients are resistant to these combination therapies.

Using a clinically guided genetic screening approach, researchers from the Perelman School of Medicine at the University of Pennsylvania identified LINP1, a lncRNA. This lncRNA is overexpressed in triple-negative breast cancer cells and regulated by the tumor suppressor p53 and the activated cell surface protein, EGFR. LINP1 enhances the repair of DNA breaks by serving as a scaffold that links two other proteins in the repair machinery.

The two repair scaffold proteins, Ku80 and DNA-PKcs, that LINP1 links coordinate the non-homologous end-joining (NHEJ) repair molecules that fix double-strand breaks in DNA. Importantly, the team found that blocking LINP1 significantly increases sensitivity by the tumor cells to radiation therapy.

The NHEJ pathway, which repairs double-strand breaks in DNA, is one of the major pathways in tumor cells that respond to radiation treatment and chemotherapeutic agents. Inhibition of the NHEJ pathway has been proposed by oncology researchers to synergize DNA-damaging therapies for better treatment outcomes for TNBCs.

"Given the important role of LINP1 in the NHEJ pathway, our study indicates that this new class of cancer-driver gene -- the lncRNAs -- may serve as unique therapeutic targets and novel biomarkers in cancer," author said. "Collectively, our study provides new insight into the DNA damage repair pathway, long non-coding RNAs, and triple-negative breast cancer."

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