August 9, 2016

How breast cancers resist chemotherapy

At a Glance

  • Researchers discovered an unexpected way that breast cancers cells with mutant BRCA1 or BRCA2 genes acquire drug resistance and evade chemotherapies.
  • Identifying how these tumors become resistant to treatment is a crucial step toward developing improved therapies.
Illustration of a replication fork Replication forks, illustrated here, are created when DNA is copied. When a fork becomes stalled by DNA damage, BRCA1 and BRCA2 protect the newly synthesized strands of DNA.ktsimage/iStock/Thinkstock

BRCA1 and BRCA2 are human proteins that help to repair damaged DNA. When either of these genes is mutated, or altered, the resulting abnormal proteins may be unable to properly repair DNA. Cells with such mutations are more likely to develop additional genetic alterations that can lead to cancer. Together, BRCA1 and BRCA2 mutations account for about 20-25% of hereditary breast cancers and 5-10% of all breast cancers. Mutations in these genes also increase the risk of ovarian and other types of cancer.

The reduced ability to repair DNA makes cancer cells with a BRCA1 or BRCA2 mutation sensitive to treatment with DNA-damaging drugs. But breast cancers eventually acquire resistance to these drugs. One way that tumors develop chemoresistance is through restoration of a DNA repair process called homologous recombination. However, scientists have recently uncovered other roles for BRCA1 and BRCA2 after DNA is damaged.

A team of researchers led by Drs. Andre Nussenzweig and Shyam Sharan at NIH’s National Cancer Institute (NCI) examined the roles of BRCA1 and BRCA2 in DNA replication, the process by which the cell copies DNA strands in preparation for cell division. Their study appeared on July 20, 2016, in Nature.

During DNA replication, the enzymes that copy DNA create structures called replication forks. The movement of a replication fork as it migrates along a DNA molecule can be disrupted by DNA damage. This interruption of replication fork migration results in what is called a stalled fork. Certain proteins are recruited to stalled forks to stabilize, repair, and restart the replication fork. Forks that aren’t repaired are degraded by other enzymes.

When a replication fork stalls, the BRCA1 and BRCA2 proteins protect the newly synthesized strands of DNA. When these proteins are absent, the replication fork is destabilized and the newly synthesized DNA is degraded. Thus, lack of BRCA1 and BRCA2 increases genomic instability and enhances sensitivity to DNA-damaging drugs.

The researchers identified several proteins that actively promote destabilization of replication forks. These proteins, which include PTIP, CHD4, and PARP1, help to recruit enzymes that degrade newly synthesized DNA. Their absence protected the DNA at replication forks and reversed the drug sensitivity of BRCA1- and BRCA2-mutant cells.

An analysis of clinical information showed that expression of PTIP correlated with how patients with BRCA1- and BRCA2-mutant cancers responded to treatment with DNA-damaging agents. Levels of these proteins might thus be a useful biomarker for predicting and tracking patient responses in the clinic.

“A deeper knowledge of the processes that drive drug resistance in BRCA1/2-mutant tumors will lead to novel therapeutic approaches that target tumor-specific vulnerabilities,” Nussenzweig adds.

Related Links

Reference: Replication fork stability confers chemoresistance in BRCA-deficient cells. Chaudhuri AR, Callen E, Ding X, Gogola E, Duarte AA, Lee JE, Wong N, Lafarga V, Calvo JA, Panzarino NJ, John S, Day A, Crespo AV, Shen B, Starnes LM, de Ruiter JR, Daniel JA, Konstantinopoulos PA, Cortez D, Cantor SB, Fernandez-Capetillo O, Ge K, Jonkers J, Rottenberg S, Sharan SK, Nussenzweig A. Nature. 2016 Jul 20;535(7612):382-7. doi: 10.1038/nature18325. PMID: 27443740.

Funding: NIH’s National Cancer Institute (NCI); U.S. Department of Defense; Netherlands Organization for Scientific Research; Dutch Cancer Society; Swiss National Science Foundation; Human Frontier Science Program; and Novo Nordisk Foundation.