Original contributionLack of expression of androgen receptor may play a critical role in transformation from in situ to invasive basal subtype of high-grade ductal carcinoma of the breast
Introduction
The role of androgen and androgen receptor (AR) in breast cancer is still uncertain. Several lines of evidence support their involvement in breast carcinogenesis. First, epidemiologic studies showed that increased serum androgen level was associated with an increased risk for breast cancer in postmenopausal patients [1]. Also, hormone replacement with combined estrogen and testosterone had a significantly higher risk for breast cancer over estrogen alone [2]. Second, AR is expressed frequently in breast carcinoma, including both invasive and in situ ductal carcinomas [3], lobular carcinoma [4], BRCA-mutated tumors [5], and mammary Paget's disease [6]. Third, expression of AR seems to correlate with better prognosis for breast carcinoma. A univariate analysis showed that AR, along with estrogen receptor (ER), tumor size, tumor grade, lymph node status, and high level of Ki-67, had prognostic power in primary breast cancer [7]. For ER-negative tumors, AR positivity was associated with significantly better disease-free survival compared with AR-negative ones [8]. Patients with AR-positive tumors were shown to have better survival after disease recurrence compared with AR-negative tumor (22 versus 12 months) [9]. Rakha et al [10] reported that in 1944 cases of invasive breast carcinomas, tumor size, lymph node stage, and AR positivity were the most useful prognostic markers, better than tumor grade, and expression of ER, progesterone receptor (PR), HER-2, epidermal growth factor receptor (EGFR), and p53. Fourth, AR may also be served as an effective therapeutic target in certain subgroup of patients. Androgen receptor–negative breast cancer had a significantly poorer response to tamoxifen therapy than AR-positive tumors [11]. Tamoxifen plus fluoxymesterone (androgen) offered some therapeutic advantage over tamoxifen alone in metastatic breast carcinoma [12]. Thus, it seems that AR is not only frequently expressed in breast carcinoma and related to prognosis, but also may serve as a predictive marker for hormone therapy and a potential therapeutic target for breast cancer, especially for ER/PR-negative breast cancer.
Several different but related molecular classifications have been developed recently. Cytokeratin (CK) classification divides tumors based on the expression of several CK markers, with basal/stem cell subtype being CK14-, CK17-, or CK5/6 positive and luminal cell subtype being CK8- or CK18 positive [13], [14], [15]. Breast carcinomas expressing stem/basal markers had worse prognosis [16], [17]. Triple-negative classification classifies tumors that are negative for ER, PR, HER-2 as basal subtype, which lack the benefit of specific target therapies such as tamoxifen, aromatase inhibitors, or Herceptin. Triple-negative phenotype has been shown to be the sole prognostic marker in lymph node–negative tumors [10]. Using ER/HER-2 classification, Matos et al [18] divided 168 cases of invasive breast carcinoma into 4 subtypes: basal (ER and HER-2−, 7.6%), basal-like HER-2 overexpression (ER− and HER-2+, 17.7%), luminal A (ER− and HER-2−, 56.3%), and luminal B (ER+ and HER-2+, 16.5%). Both basal and basal-like types were mostly grade 3 tumors, frequently p-cadherin-, p63-, and CK5-positive. This classification aims to provide better guidances for specific target therapy. Others showed that a combination of CK markers and ER/PR/HER-2 expression may provide a molecular classification that is more related to the classification defined by gene expression profiling data than using either CK markers or ER/PR/HER-2 alone [19], [20].
These previous studies have established a potential role of AR in breast cancer. However, its relationships with tumor progression, tumor grades, and these molecular classifications are not clearly defined. In this study, we explored the potential role of AR in breast cancer by analyzing the relationship of its expression with tumor progression (ductal carcinoma in situ [DCIS] versus invasive ductal carcinoma [IDC]); tumor cell nuclear grades (high grade [HG] versus non–high grade [NHG]); expression of ER, PR, and HER-2; and 3 currently used molecular classifications in 184 cases of DCIS and IDC.
Section snippets
Methods
Ninety-four cases of DCIS and 90 cases of IDC were retrieved from the files of the Pathology Department at Strong Memorial Hospital and divided into HG and NHG subgroups (HG-DCIS, NHG-DCIS, HG-IDC, and NHG-IDC) using standard nuclear grading criteria [21], [22]. High-grade carcinomas were defined as tumor cells with high nuclear grade including pleomorphism, coarse chromatin patterns, prominent nucleoli, and large nuclear size (>2 red blood cells), whereas NHG carcinomas were defined as tumors
Expression of AR, along with ER and PR, with tumor progression and tumor grade
Like ER and PR, majority of the NHG carcinoma expressed AR regardless of either in situ (89%) or invasive carcinoma (92%), suggesting that AR, along with ER and PR, may be important for the carcinogenesis of NHG carcinoma, but not essential for the transformation from NHG-DCIS to NHG-IDC (Table 3). In HG carcinoma, although there was no significant difference in the rates of ER and PR expression between HG-DCIS (23%-30%) and HG-IDC (18%-25%) (P = .2179 and 1.0000), there is significant
Discussion
Androgen receptor is a nuclear transcriptional factor. After binding to dihydrotestosterone, an active form of androgen converted from testosterone by 5α-reductase in the cytoplasm, AR dimerizes, translocates into the nucleus, binds to the androgen-response elements on DNA and activates genes involved in cell growth and cell death. Besides androgen, AR can also be activated by androgen-independent pathways through mechanisms such as mutation, overexpression, posttranslational modification of AR
Acknowledgment
The authors wish to thank Dr Steven Hajdu for his encouragement and critical suggestions.
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