Abstract
Triple negative breast cancers are a heterogeneous group of tumors characterized by poor patient survival and lack of targeted therapeutics. Androgen receptor has been associated with triple negative breast cancer pathogenesis, but its role in the different subtypes has not been clearly defined. We examined androgen receptor protein expression by immunohistochemical analysis in 678 breast cancers, including 396 triple negative cancers. Fifty matched lymph node metastases were also examined. Association of expression status with clinical (race, survival) and pathological (basal, non-basal subtype, stage, grade) features was also evaluated. In 160 triple negative breast cancers, mRNA microarray expression profiling was performed, and differences according to androgen receptor status were analyzed. In triple negative cancers the percentage of androgen receptor positive cases was lower (24.8% vs 81.6% of non-triple negative cases), especially in African American women (16.7% vs 25.5% of cancers of white women). No significant difference in androgen receptor expression was observed in primary tumors vs matched metastatic lesions. Positive androgen receptor immunoreactivity was inversely correlated with tumor grade (p<0.01) and associated with better overall patient survival (p = 0.032) in the non-basal triple negative cancer group. In the microarray study, expression of three genes (HER4, TNFSF10, CDK6) showed significant deregulation in association with androgen receptor status; eg CDK6, a novel therapeutic target in triple negative cancers, showed significantly higher expression level in androgen receptor negative cases (p<0.01). These findings confirm the prognostic impact of androgen receptor expression in non-basal triple negative breast cancers, and suggest targeting of new androgen receptor-related molecular pathways in patients with these cancers.
Highlights
The prognostic role of hormone receptors has widespread acceptance in the management of breast cancer
Androgen receptor expression is down-regulated in triple negative breast cancers (TNBCs)
androgen receptor (AR) was significantly down-regulated in TNBC samples (Figure 2A; p,0.001), and up-regulated in HER2 positive cases (Figure 2B; p = 0.025), as well as in estrogen receptor a (ER) and progesterone receptor (PR) positive cases (Figure 2C–D; p,0.001 both)
Summary
The prognostic role of hormone receptors has widespread acceptance in the management of breast cancer. In ER-positive luminal breast cancers, AR has a growth inhibitor role but AR signaling may promote growth of a subset of ER-negative AR-positive breast cancers [1,2,9,10,16]. On these bases, clinical trials (ClinicalTrials.gov) have been established focusing on AR targeting in ER-negative cases, such as triple negative breast cancers (TNBCs) [13,17]
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