BAG-1 Overexpression Has a ‘Paradoxical’ Association With Improved Breast Cancer Survival

SAN ANTONIO—Overexpression of the antiapoptotic protein BAG-1 has a seemingly paradoxical association with improved survival in breast cancer, according to a study reported at the 22nd Annual San Antonio Breast Cancer Symposium.

A retrospective analysis of patients with early-stage breast cancer showed that BAG-1-positive patients had an 81% 10-year overall survival, compared with 43% for BAG-1-negative patients.

“Why would a protein that is anti-apoptotic and promotes cell proliferation and survival be associated with good survival in breast cancer patients?” asked Bruce Turner, MD, PhD, a radiation oncologist at Thomas Jefferson University, Philadelphia. “A number of hypotheses have been offered, but the bottom line is, we don’t know. Perhaps the answer lies in laboratory studies showing that overex-pression of BAG-1 in breast cancer cells may inhibit metastases. Why this occurs likely depends on unrecognized functions of these proteins.”

BAG-1 is a multifunctional protein that first attracted investigators’ attention because of its ability to form complexes with the antiapoptotic protein Bcl-2 and inhibit cell death, Dr. Turner said. BAG-1 has multiple isoforms, including BAG-1 long and BAG-1 short. The long isoform is a nuclear protein, whereas BAG-1 short is located in the cytoplasm, suggesting that the two isoforms may have different functions, he said.

The investigators, led by Dr. Turner and John C. Reed, MD, PhD, scientific director of the Burnham Institute, developed a monoclonal antibody specific for the cytosolic short isoform of BAG-1. They retrospectively evaluated a cohort of 116 breast cancer patients for the presence and distribution of BAG-1 short in pathology specimens. The researchers then correlated BAG-1 expression with various survival parameters.

The patients were treated at Yale University from the late 1970s through 1989. All the patients had early-stage breast cancer, and tumor size averaged 1.8 cm. About half the patient population had axillary lymph node dissection, and 42% of these patients had pathologically negative lymph nodes. Nodal status was unknown in the remaining patients, Dr. Turner said.

Pathology slides were read by a pathologist and scored on the basis of staining intensity (0 to 4) and distribution of immunopositive cells (0% to 100%). The intensity score multiplied by the staining distribution percentage identified positive patients at a cutoff of 150 or higher.

Study Results

“When we looked at cytosolic levels of BAG-1 in normal breast epithelium, we saw 11% staining,” Dr. Turner said. “When we looked at invasive breast cancer, we found 66% staining, indicating a clear upregulation of BAG-1. We did not see upregulation of BAG-1 in the nucleus. As others have reported, we found upregulation of Bcl-2 as we went from benign epithelium to invasive breast cancer.”

BAG-1 overexpression was associated with significantly improved 10-year overall survival—81% vs 43% in patients who were BAG-1 negative—and a significantly improved 10-year distant-metastasis-free survival (78% vs 33%) (see Table). Median follow-up for the entire cohort was more than 13 years.

“Interestingly,” Dr. Turner said, “when we did a subset analysis and looked at those patients who were axillary lymph node negative, we again found significant differences in survival in women with breast tumors that overexpressed BAG-1, compared to those with tumors expressing low levels of BAG-1.”

In a multivariate analysis of various prognostic markers, elevated levels of BAG-1 were significantly associated with an improved overall, distant-metastasis-free, and cause-specific survival in both the overall cohort and in patients with lymph-node-negative breast tumors.

Also, in the multivariate analysis, overexpression of Bcl-2 was shown to be an independent predictor of cause-specific survival, with a trend toward an association with overall survival. Tumor stage correlated with all three survival parameters. However, hormone receptor status, p53 status, and HER-2/neu status had no significant correlation with any survival parameter.