BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast

Abstract

BAG-1 (bcl-2-associated athanogene) enhances oestrogen receptor (ER) function and may influence outcome and response to endocrine therapy in breast cancer. We determined relationships between BAG-1 expression, molecular phenotype, response to tamoxifen therapy and outcome in a cohort of breast cancer patients and its influence on tamoxifen sensitivity in MCF-7 breast cancer cells in vitro . Publically available gene expression data sets were analysed to identify relationships between BAG-1 mRNA expression and patient outcome. BAG-1 protein expression was assessed using immunohistochemistry in 292 patients with invasive ductal carcinoma and correlated with clinicopathological variables, therapeutic response and disease outcome. BAG-1-overexpressing MCF-7 cells were treated with antioestrogens to assess its effects on cell proliferation. Gene expression data demonstrated a consistent association between high BAG-1 mRNA and improved survival. In ER+ cancer ( n =189), a high nuclear BAG-1 expression independently predicted improved outcome for local recurrence ( P =0.0464), distant metastases ( P =0.0435), death from breast cancer ( P =0.009, hazards ratio 0.29, 95% CI: 0.114–0.735) and improved outcome in tamoxifen-treated patients ( n =107; P =0.0191). BAG-1 overexpression in MCF-7 cells augmented antioestrogen-induced growth arrest. A high BAG-1 expression predicts improved patient outcome in ER+ breast carcinoma. This may reflect both a better definition of the hormone-responsive phenotype and a concurrent increased sensitivity to tamoxifen.

Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer

“…The relationship between PUMA mRNA expression and breast cancer outcome was explored using pub- (Millar et al, 2008). Examination of the distribution frequency of PUMA mRNA showed a normal distribution that was dichotomized using the median value (0), into high or low expressing groups.…”

“…PUMA expression by immunohistochemistry and patient outcome PUMA protein expression was assessed by immunohistochemistry using tissue microarrays (TMAs) constructed from tumors from a cohort of 292 patients diagnosed with invasive ductal breast carcinoma (Millar et al, 2008). From our original cohort of patients, 268 invasive ductal carcinomas were available for analysis because of loss of some tissue cores during processing of the TMAs.…”

“…The data set from the Nederlands Kanker Instituut and designated the NKI cohort, comprised 295 patients, 76% of which were ER þ , with a median follow-up of 93.6 months (range 0.6-220 months) and was of similar clinicopathological composition to our clinical cohort. Data were generated using Rosetta NKI-spotted oligonucleotide arrays and were downloaded from http://microarray-pubs.stanford.edu/wound_ NKI/explore.html as log 2-transformed values in a text table format, as previously described (Millar et al, 2008). Raw data were directly transferred to the final output file without further processing.…”

“…This cohort has been previously described in more depth elsewhere (Millar et al, 2008). Briefly, the cohort consists of cases of invasive ductal carcinoma of no special type, median age 54 (range 24-87) with a median follow-up of 64 months (range 0-152.1).…”

“…This apoptotic signature not only predicted response to TAM in breast cancer patients, but was predictive independent of the proliferative signature, providing strong evidence that aberrations in pathways driving apoptosis/survival define a distinct, clinically-relevant mechanism of the endocrine responsiveness in a subset of patients . Indeed, our more recent studies have demonstrated that individual genes mediating cellular survival, such as BAG-1 can predict outcome and TAM responsiveness in breast cancer patients (Millar et al, 2008), with in vitro evidence that they may also have a role early on in breast cancer development (Anderson et al, 2010).…”