New Insight into the Biology of the BRCA1 Breast Cancer Gene

Newswise — Studies have well established that women who harbor a mutation in the BRCA1 tumor suppressor gene are at greater risk for developing breast and ovarian cancers. Less known is information on other molecular events that may impact cancer formation in cells having a BRCA1 mutation. Investigators from The Cancer Institute of New Jersey (CINJ) and a number of major cancer centers in Europe have identified the role a key protein plays in helping cells with mutant BRCA1 genes to survive. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

BRCA1 helps ensure the stability of a normal cell’s genetic makeup (DNA) by creating a protein that helps repair DNA damage. It is a mutated form of this gene that investigators explored in this latest research (53bp1 Loss Rescues BRCA1 Deficiency and is Associated with Triple-Negative and BRCA-Mutated Breast Cancers), which is published in the current online edition of Nature Structural & Molecular Biology.

Women with a BRCA1 mutation have one normal copy of the gene inherited from one parent, and one mutant copy inherited from the other parent. The cancers that arise lose the normal copy, thus also losing all tumor-suppressing function of the BRCA1 gene. The breast cancers arising in women with BRCA1 mutations are mostly classified as “triple-negative”, lacking expression of the estrogen receptor, the progesterone receptor, and the HER2 gene. One observation that has puzzled researchers is that normal cells are unable to tolerate losing BRCA1, but tumor cells have evolved to be able to survive without BRCA1. Researchers at CINJ, together with collaborators at the Netherlands Cancer Institute, the Cancer Research UK-MRC Gray Institute for Radiation Oncology and Biology in the United Kingdom, the Danish Cancer Society in Copenhagen, and others have found some insight into this issue.

A screen was performed to determine what genetic events would allow normal cells to tolerate loss of functional BRCA1. It was found that loss of another DNA repair protein, 53BP1 (p53 Binding Protein 1) allows cells to continue growing after loss of BRCA1. Moreover loss of normal production of the 53BP1 protein was found in a subset of BRCA1-associated cancers and in sporadic “triple-negative” breast cancers in two independent breast cancer patient cohorts from the United States and Finland. According to the investigators, these data suggest that loss of 53BP1 may allow cells to tolerate loss of BRCA1, and that some breast cancers may have acquired loss of 53BP1 protein expression.

CINJ medical oncologist Shridar Ganesan, MD, PhD, assistant professor of medicine and pharmacology at UMDNJ-Robert Wood Johnson Medical School, is one of the senior authors on the study. “Loss of 53BP1 in breast cancer cells may give some clue to their underlying biology, and may ultimately impact their responsiveness to certain chemotherapeutic agents that are being used to treat these aggressive cancers,” he noted. “This is especially true regarding platinum-based drugs as well as a new class of agents known as PARP inhibitors, as cancers arising in women with BRCA mutations have been shown to be sensitive to these specific treatments. We hope to ultimately be able to predict why some patients respond well to these treatments and others are resistant. This work was the result of a group effort involving the laboratories of Jos Jonkers, Madelana Tarsounas and Jiri Bartek in Europe, and shows the importance of international collaborations in advancing cancer research.”

The authors on the study are: Peter Bouwman, Netherlands Cancer Institute; Amal Aly, CINJ; Jose M. Escandell, The Cancer Research UK-MRC Gray Institute for Radiation Oncology and Biology; Mark Pieterse, Netherlands Cancer Institute; Jirina Bartkova, Danish Cancer Society; Hanneke van der Gulden, Netherlands Cancer Institute; Sanne Hiddingh, Netherlands Cancer Institute; Maria Thanasoula, The Cancer Research UK-MRC Gray Institute for Radiation Oncology and Biology; Atul Kulkarni, CINJ; Qifeng Yang, CINJ; Bruce G. Haffty, CINJ; Johanna Tommiska, Helsinki University Central Hospital; Carl Blomqvist, Helsinki University Central Hospital; Ronny Drapkin, Dana-Farber Cancer Institute; David J. Adams, Wellcome Trust Sanger Institute; Heli Nevanlinna, Helsinki University Central Hospital; Jiri Bartek, Danish Cancer Society and Palacky University; Madalena Tarsounas, The Cancer Research UK-MRC Gray Institute for Radiation Oncology and Biology; Ganesan, CINJ; and Jos Jonkers, Netherlands Cancer Institute.

The study was supported by funding from the Dutch Cancer Society, the Netherlands Organization for Scientific Research and the European Community 7th Framework Program (Jonkers); Cancer Research UK and Breast Cancer Campaign (Tarsounas); U.S. Department of Defense (Aly); the National Cancer Institute, the Sidney Kimmel Foundation, and the Breast Cancer Research Foundation (Ganesan); the Breast Cancer Research Foundation and the National Cancer Institute (Haffty); the Danish Cancer Society, the Danish National Research Foundation, Vilhelm Pedersen and Hustrus Mindelegat, the Czech Ministry of Education, and the European Community 7th Framework Program (Bartek); the Helsinki University Central Hospital Research Fund, the Finnish Cancer Society, the Academy of Finland and the Sigrid Juselius Foundation (Nevanlinna).

About The Cancer Institute of New JerseyThe Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

The CINJ Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, Cooper University Hospital and Jersey Shore University Medical Center. Affiliate Hospitals: Bayshore Community Hospital, CentraState Healthcare System, JFK Medical Center, Mountainside Hospital, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate