The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically validated primary breast cancer cohorts [training cohort, n = 219; validation cohort, n = 418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively]. The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22 of 46 (48%) previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1% nor 10% cut-points were robustly prognostic. ROC analysis revealed that a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR, 0.41; P = 0.015) and validation (HR, 0.50; P = 0.014) cohorts. Tenfold cross-validation confirmed the robustness of this AR cut-point. Patients with ERα-positive tumors and AR positivity ≥78% had the best survival in both cohorts (P 0.87) had the best outcomes (P < 0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer

Elevated levels of tumour apolipoprotein D independently predict poor outcome in breast cancer patients

Aims: Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-α (ERα) expression and androgen receptor (AR) expression in predicting breast cancer outcome. Methods and results: ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERα expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with (≥1%) ERα-positive cancers with low (<20.7%) ApoD positivity, or those showing high (≥78%) AR positivity and low (<20.7%) ApoD positivity had better OS than other patient groups. Conclusions: ApoD expression could be used to predict breast cancer prognosis independently of ERα and AR expression

Elevated levels of tumour apolipoprotein D independently predict poor outcome in breast cancer patients

Aims: Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-α (ERα) expression and androgen receptor (AR) expression in predicting breast cancer outcome. Methods and results: ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERα expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with (≥1%) ERα-positive cancers with low (<20.7%) ApoD positivity, or those showing high (≥78%) AR positivity and low (<20.7%) ApoD positivity had better OS than other patient groups. Conclusions: ApoD expression could be used to predict breast cancer prognosis independently of ERα and AR expression

The biological role and regulation of versican levels in cancer

Increased expression of the proteoglycan, versican is strongly associated with poor outcome for many different cancers. Depending on the cancer type, versican is expressed by either the cancer cells themselves or by stromal cells surrounding the tumor. Versican plays diverse roles in cell adhesion, proliferation, migration and angiogenesis, all features of invasion and metastasis. These wide ranging functions have been attributed to the central glycosaminoglycan-binding region of versican, and to the N-(G1) and C-(G3) terminal globular domains which collectively interact with a large number of extracellular matrix and cell surface structural components. Here we review the recently identified mechanisms responsible for the regulation of versican expression and the biological roles that versican plays in cancer invasion and metastasis. The regulation of versican expression may represent one mechanism whereby cancer cells alter their surrounding microenvironment to facilitate the malignant growth and invasion of several tumor types. A greater understanding of the regulation of versican expression may contribute to the development of therapeutic methods to inhibit versican function and tumor invasion.Carmela Ricciardelli, Andrew J. Sakko, Miranda P. Ween, Darryl L. Russell and David J. Horsfal