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Triple-negative breast cancer target identified
An FDA-approved drug curbs tumor growth in a mouse model of a deadly form of breast cancer. Luika Timmerman, PhD, showed that growth of about one-third of triple-negative breast cancers overproduce a cell-surface protein called xCT (green), which she targeted with an FDA-approved drug to slow tumor growth. Timmerman described her discovery in a study published online on Oct. 3 in the journal Cancer Cell.
Difficulty of Treating Triple-Negative Breast Cancer
However, triple-negative breast cancers are difficult to treat effectively because they do not make either of these receptors. To treat patients with triple-negative breast cancer, physicians instead use older chemotherapies that produce side effects in normal tissues, thus limiting the doses that patients can receive.
“This study of human tumors in mice and of breast cancer cell lines demonstrates the potential of targeting not only this cystine transporter, but also other metabolic abnormalities in cancer,” Timmerman said.
Abnormal Metabolic Behavior of Cancer Cells
“Different cancers seem to acquire different metabolic abnormalities that might in some cases give them a growth or survival advantage,” she said.
“One of the strengths of this study was the large number of different cell lines I was able to test. When I saw similar results in many samples, I felt I was looking at a fundamental metabolic behavior that we could exploit to specifically target triple-negative tumors that overexpress the xCT cystine transporter, a significant group of previously untargettable tumors.”
Timmerman initially focused on investigating the metabolism of the amino acid glutamine among different breast cancer-derived cell lines because glutamine metabolism was long known to be perturbed in cancer. She matched genetic “microarray” data that tracks gene activity to functional differences among tumors and tumor cell lines in culture.
But she also measured amino acids and other molecules in cell culture to detect metabolic changes. When she did so, she noticed that cystine and glutamate levels are frequently correlated in triple-negative cancers.
“We have identified a compelling therapeutic target commonly expressed by breast tumors of poorest prognosis, and a lead compound for rapid, effective drug development,” Timmerman adds.
A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.
Timmerman conducted many of her experiments using breast cancer cell lines obtained from a large collection developed by one of the senior authors, Joe Gray, PhD, formerly head of the breast oncology program at UCSF and currently associate director for translational research for the Knight Cancer Institute at Oregon Health & Science University in Portland.
Before leading her own lab, Timmerman began her cancer metabolism studies working as a postdoctoral fellow in the lab of another senior author, Frank McCormick, PhD, FRS, director of the UCSF Helen Diller Family Comprehensive Cancer Center.
Additional study authors include UCSF researchers Raymond Louie, PhD, Merce Padro, Anneleen Daemen, Denise Chan, PhD, and Laura van’t Veer, PhD; Mariia Yuneva of the MRC National Institute of Medical Research in London; Thomas Holton from San Francisco State University; Min Hu from the Novartis Institutes for BioMedical Research in Shanghai; Stephen Ethier from the University of South Carolina; and Kornelia Polyak from the Dana-Farber Cancer Institute. The research was funded by the National Institutes of Health, the Bay Area Breast Cancer SPORE, the Durra Family Fund, the Mount Zion Health Fund, and the Prospect Creek Foundation.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.
Original press releas: http://www.ucsf.edu/news/2013/10/109376/scientists-identify-triple-negative-breast-cancer-target-drug-development