[Lani]

Researchers Isolate Importance of Gene in Determining How Aggressive a Patient's Breast Cancer Will Be
[Oregon Health & Science University]
Oregon Health & Science University Knight Cancer Institute researchers found that the GRB7 gene drives an aggressive form of breast cancer and acts independently of the HER-2 gene, known to be a stimulator of breast cancer growth. Isolating the role of this gene could ultimately help fine-tune a patient's treatment and enable physicians to provide a more accurate prognosis.

The study, published online this month by Breast Cancer Research and Treatment, established that levels of GRB7, or growth factor receptor bound protein seven, are important on their own as a marker for aggressive breast cancer. Previously it was understood that patients whose breast cancer tumors tested positive for high levels of HER-2, the protein human epidermal growth factor receptor-2, tended to have a more aggressive form of the disease than patients whose tumors did not have elevated levels of this protein. However, OHSU Knight Cancer Institute researchers found that the protein driving this aggressive form of the disease is GRB7 rather than HER-2 on its own.

"Our work shows GRB7 protein levels are an important and independent factor in determining a prognosis for breast cancer," said OHSU Knight Cancer Institute member Shiuh-Wen Luoh, M.D., Ph.D., assistant professor of medicine in the Division of Hematology and Medical Oncology, medical oncology director for the Comprehensive Breast Cancer Clinic and senior author of the paper.

The findings could have implications for the types of therapies used. Luoh said a next step will be to determine if high levels of the GRB7 protein influence patient responses to anti-HER-2 therapies such as Herceptin or Tykerb.

The research into GRB7's role is advancing the OHSU Knight Cancer Institute's mission to provide cancer patients with personalized treatments that target the specific characteristics of their disease.

"Our work was only made possible with the availability of a breast tumor repository that OHSU and the Knight Cancer Institute began collecting about 20 years ago," said Ed Keenan, Ph.D., who served as co-investigator on the study. Keenan, former associate dean of medical education for OHSU's School of Medicine, is a professor in the Department of Physiology and Pharmacology and the Department of Surgery. He also serves as president of The Foundation for Medical Excellence.

Other researchers who worked on the paper, titled "GRB7 protein over-expression and clinical outcome in breast cancer," were Betsy Ramsey, B.S., research associate, OHSU Knight Cancer Institute and Department of Physiology and Pharmacology; Tao Bai, B.S., research associate, Division of Hematology and Medical Oncology; Amy E. Hanlon Newell, Ph.D., senior research associate, Department of Molecular and Medical Genetics; Megan Troxell, M.D, Ph.D., associate professor, Department of Pathology; Byung S. Park, Ph.D., research assistant professor, Division of Biostatistics, Department of Public Health and Preventive Medicine; and Susan B. Olson, Ph.D., FACMG, professor, Department of Molecular and Medical Genetics and director of the Clinical & Research Cytogenetics Laboratories.

The study was funded by the Department of Veterans Affairs, Portland VA Research Foundation, OHSU Presidential Bridge Award and OHSU Foundation.

ABSTRACT: GRB7 protein over-expression and clinical outcome in breast cancer
[Breast Cancer Research and Treatment]
The growth factor receptor-bound protein-7 gene (GRB7) encodes a multi-domain signal transduction molecule. The purpose of this study was to examine the clinical significance of GRB7 protein expression in human breast cancer. Western blotting analysis of protein extracts from 563 annotated frozen breast tumors was performed. Expression status of GRB7 and HER-2 was correlated with clinical covariates and outcomes. Cox proportional hazards were used to identify factors associated with breast cancer-free interval. The median follow-up was 71 months. P values <0.05 were considered statistically significant (two-sided). A discrepancy between HER-2 and GRB7 protein over-expression was observed. GRB7 protein over-expression was associated with negative estrogen and progesterone receptor status, higher tumor grade, larger primary tumor size, (more) axillary lymph node involvement, higher clinical stage, and shortened breast cancer-free interval. HER-2 protein over-expression was associated only with higher tumor grade. Multi-variate analysis revealed that GRB7 protein over-expression was an independent adverse prognostic factor for breast cancer-free interval (hazard ratio 1.69, 95% confidence interval 1.07-2.67; P = 0.024). The same was true of the subset of patients who did not receive any adjuvant systemic therapy (hazard ratio 1.68, 95% confidence interval 1.16-2.31; P = 0.0055). Using FISH analysis, 32/32 (100%; 95% CI 89-100%) tumors which over-expressed both HER-2 and GRB7 proteins and 1/35 (3%; 95% CI 0-15%) tumors with HER-2 but no GRB7 protein over-expression with Western blotting analysis demonstrated HER-2 gene amplification. GRB7 protein over-expression is an independent adverse prognostic factor in human breast cancer.