Positive Androgen Receptor Expression Research Articles

Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer

Treatment of triple-negative invasive breast cancers, defined by the absence of estrogen and progesterone receptors and c-erbB2 expression, remains challenging. Androgen receptor, a member of the nuclear receptor superfamily that is involved in signaling pathways regulating cell proliferation, has been implicated in breast tumorigenesis. We immunohistochemically examined the expression of androgen receptor, basal markers (CK14, 34βE12) and EGFR in 699 triple-negative invasive breast cancers in tissue microarrays using the streptavidin–biotin method, and correlated the findings with clinical outcome. Positive androgen receptor expression was defined as staining of 1% or more of tumor cell nuclei. Survival outcomes were estimated with the Kaplan–Meier method and compared between groups with log-rank statistics. Cox proportional hazards models were used to determine the effect of androgen receptor on survival outcomes. Immunohistochemical positivity was observed in 38% of tumors, with the proportion of stained tumor cells ranging from 1 to 95% (mean 29%, median 10%). Androgen receptor expression was inversely associated with histologic grade and mitotic score. CK14, 34βE12 and EGFR confirmed 85% of cases to be basal-like, without significant association of basal-like phenotype with androgen receptor expression. Disease-free survival was significantly better in androgen receptor-positive triple-negative breast cancer, with a trend for improved overall survival. Decreased recurrence likelihood in both triple-negative and basal-like tumors (hazard ratio, 0.704; 95% confidence intervals, 0.498–0.994; P=0.0464; and hazard ratio, 0.675; 95% confidence intervals, 0.468–0.974; P=0.0355, respectively) was noted within 5 years of diagnosis but not thereafter. Our study suggests that loss of androgen receptor in triple-negative breast cancers augurs a worse prognosis, including those with basal-like features. More work in elucidating its relationship with mechanisms of progression, as well as trials of targeted treatment for androgen receptor-expressing triple-negative tumors, needs to be performed.

Androgen Receptor-Positive Triple Negative Breast Cancer: A Unique Breast Cancer Subtype

The significance of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is unclear, and published studies so far have been inconclusive. A tissue microarray was constructed using tissue obtained from 119 patients with primary TNBC and stained for AR expression. Other tissue types obtained included recurrent TNBC, normal breast tissue, adjacent ductal carcinoma-in situ (DCIS), lymph node (LN) and distant metastases. Positive AR expression was defined as ≥10% nuclear staining. Epithelial tissue was present and evaluable in 94 TNBC patients with a total of 177 tissue cores. AR expression in TNBC was 22 of 94 (23%). AR expression was higher in normal breast tissue (88%) and adjacent DCIS (73% overall). All LN metastases from AR-positive TNBC patients were also AR positive; in addition, no AR-negative TNBC patient had AR-positive LNs. AR expression was associated with older patient age (63 vs. 57 years, respectively, p = 0.051) and LN metastases (p = 0.033). Locoregional recurrence and overall/disease-specific survival were similar between AR-positive and AR-negative patients, although AR-positive patients had more advanced disease. On multivariate analysis, the presence of LN metastases was associated with poorer recurrence-free survival in AR-positive patients (hazard ratio, 4.34) (p = 0.031). The AR is expressed in normal breast tissue, and expression decreases with advancement to DCIS and invasive cancer. AR-positive TNBC was more common in older patients and had a higher propensity for LN metastases. AR-positive TNBC may represent a breast cancer subtype with unique features that may be amenable to treatment with alternative targeted therapies.

Immunohistochemical Study on Androgen Receptors in the Anterior Cruciate Ligament in Dogs

Androgen is closely involved as the cause of rupture of anterior cruciate ligament (ACL) in human. In dogs, however, factors contributing to rupture of ACL remain unknown. In this study, expression of androgen receptor (AR) and histological distribution of blood vessels in ACL, and serum testosterone concentration were investigated in relation with age and sex to confirm whether canine ACL is an androgen-responsive tissue. Materials of ACL were obtained from 26 dogs: 12 young female Beagles, 2 old female mixed breeds, 9 young male Beagles, and 3 old male mixed breeds. In all canine ACL, positive AR expression was recognized in the nuclei of the fibrocytes, fibroblasts, synovial cells, and vascular endothelial cells of ACL. Expressions of AR were lesser in old males compared to the young males; however, females had no age difference in expression. Distributions of blood vessels in the synovial membrane of the ligament were fewer in old dogs both of males and females than youngs. Although distributions of vessels in the interstitium were apparently fewer in young females. Serum testosterone concentration was significantly higher in young males. Females had no age difference in the levels. From these results, it is suggested that canine ACL is an androgen-responsive tissue, and this consideration seems to closely relate to the epidemiological background that the incidence of rupture of ACL of dogs is higher in females than in males.

Abstract P3-10-03: The Implication of Androgen Receptor Expression in Breast Cancers

Abstract Purpose: To evaluate the implication of androgen receptor (AR) expression in patients with breast cancer. Methods: Immunohistochemically AR expression was investigated in 931 invasive breast cancers prepared in tissue microarray blocks that were collected in between November 1999 and August 2005. The clinicopathological features, disease-free (DFS) and overall survival (OS) were analyzed using chi-square test, Kaplan-Meier methods, and Cox's models. Tumors with ≥10% nuclear-stained cells were considered to be positive for AR, estrogen receptor (ER), and progesterone receptor (PR) expression and 3+ with immunohistochemical staing or FISH + were considered positive for HER2 expression. Results: The positive expression of AR, ER, PR, and HER2 was 58.1%, 72.2%, 61.4%, and 24.7% of all patients, respectively. AR expression was significantly associated with an older age at diagnosis (p=0.007), smaller tumor size (P<0.001), well differentiation (P<0.001), higher hormone receptors expression (P<0.001), non-triple-negative breast cancers (non-TNBC) (P<0.001), and lower proliferation index (P<0.001). In ER-negative cancers, AR expression was associated with well differentiation, lower Ki-67 index, and distinctively HER2 overexpression. With median follow-up duration of 72.7 months, AR was significantly associated with better DFS (p=0.023) and OS (p=0.048) and the association was same in ER-positive cancers but was disappeared in ER-negative cancers. In Cox's models, AR expression was an independent prognostic factor for DFS (hazard ratio, 0.654; p=0.049), but it did not reach a statistical significance for OS (hazard ratio, 0.647; p=0.119) even in ER-positive tumors. Interestingly, tumors with molecular apocrine features (ER-negative, AR-positive, and HER2-positive) showed a trend of poorer outcome with AR expression, but there was no impact of AR expression on the survival in 156 patients with TNBC. Conclusions: AR expression is significantly associated with favorable clinicopathological features and better outcomes in ER-positive cancers but tumors with molecular apocrine features showed a trend of poorer outcome with AR expression. These results suggest that AR expression could be an additional marker for endocrine responsiveness in ER-positive tumors and a target molecule for the molecular apocrine tumors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-03.

RERG (Ras-like, oestrogen-regulated, growth-inhibitor) expression in breast cancer: a marker of ER-positive luminal-like subtype

Global gene expression profiling studies have classified breast cancer into a number of distinct biological and molecular classes with clinical relevance. The heterogeneous luminal group, which is largely characterised by oestrogen receptor (ER) expression, appears to contain distinct subgroups with differing behaviour. In this study, we analysed 47,293 gene transcripts in 128 invasive breast carcinomas (BC) using Artificial Neural Networks and a cross-validation analysis in combination with an ensemble sample classification to identify genes that can be used to subclassify ER+ luminal tumours. The results were validated using immunohistochemistry on TMAs containing 1,140 invasive breast cancers. Our results showed that the RERG gene is one of the highest ranked genes to differentiate between ER+ luminal-like and ER- non-luminal cancers based on a 10-fold external cross-validation analysis with an average classification accuracy of 89%. This was confirmed in our protein expression studies that showed RERG positive associations with markers of luminal differentiation including ER, luminal cytokeratins (CK19, CK18 and CK7/8) and FOXA1 (P = 0.004) and other markers of good prognosis in BC including small size, lower histologic grade and positive expression of androgen receptor, nuclear BRCA1, FHIT and cell cycle inhibitors p27 and p21. RERG expression was inversely associated with the proliferation marker MIB1 (P = 0.005) and p53. Strong RERG expression showed an association with longer breast cancer specific survival and distant metastasis free interval in the whole series as well as in the ER+ luminal group and these associations were independent of other prognostic variables. In conclusion, we used novel bioinformatics methods to identify candidate genes to characterise ER+ luminal-like breast cancer. RERG gene is a key marker of the luminal BC class and can be used to separate distinct prognostic subgroups.

Age Dependent Expressiones of Androgen Receptores in Testes and Epididymes of Mandarin Voles（<I>Lasiopodomys mandarinus</I>）

In order to investigate the effects of age on androgen receptor (AR) in testes and epididymides of mandarin voles（Lasiopodomys mandarinus）, the expression of AR from five age groups [postnatal 1(neonatal), 10, 25, 45 and 60 days (adult) of age] was examined using immunohistochemistry method. The results were as follows: ① There was AR expression in leydig cells in neonatal voles and the expression of AR decreased at postnatal 10 days and 25days. AR expression reached its peak at postnatal 45 days and then decreased in adults（P＜0.05）. ② The positive expression of AR in myoid cells was found from neonatal to adult. The positive expression of AR was unchanged at postnatal 1 day and postnatal 10 days, but decreased at postnatal 25 days, reaching its highest level at postnatal 45 days and then decreased in adults (P＜0.05). ③ The positive expression of AR in prospermatogonia was weak in neonatal voles. There was no expression of AR in spermatogonia at postnatal 10 days. There was AR expression in spermatoon at postnatal 25 days, while in spermatocyte and some spermatoon at postnatal 45days. The positive expression of AR in spermatogonia, spermatoon and sperm was also found in adults. ④ The positive expression of AR in sertoli cells was found in adults, but there were few expressions of ARs at other ages. ⑤ The positive cells of ARs were both detected in epithelium cells and stroma cells of epididymides. These results suggest that AR expressiones in leydig cells, myoid cells and spermatogenic cells change significantly with mandarin vole’s individual development. Androgen facilitates leydig cells differentiation during puberty, and myoid cells play an important role during spermatogenesis. Androgen may regulate function of epididymises.

Expression of ER and AR in lung cancer.

Epidemiology of lung cancer differs between sexes and it might be partially explained by different sex hormone levels in women and men. There are some epidemiological data indicating that gender is a significant, independent prognostic factor in lung cancer. The aim of this study is to determine expression of ER (estrogen receptor) and AR (androgen receptor) in lung cancer, and evaluate the relationship between their expression and clinical or pathologic characteristics. Immunohistochemistry assay was used to detect expression of ER and AR. Positive expression of ER and AR were 14.3%(15/105) and 20%(21/105). Positive expression of ER had no relationship with age, gender, pathology, histological differentiation, TNM staging, size of tumor and lymph node metastasis. Although age, gender, pathology, histological differentiation and size of tumor had no effect on the expression of AR, positive rate of AR in staging III lung cancer was significantly higher than that in staging I lung cancer. The different AR expression was significant between N0 and N2 lymph node metastasis (Chi-Square= 4.7828, P=0.0287). The expression of ER has no relationship with biological behavior. Positive expression of AR may be correlated with the progression and the lymph node metastasis of lung cancer.

NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss

We demonstrate that PTEN loss causes reduced NKX3.1 expression in both murine and human prostate cancers. Restoration of Nkx3.1 expression in vivo in Pten null epithelium leads to decreased cell proliferation, increased cell death, and prevention of tumor initiation. Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. Consistent with its tumor suppressor functions, NKX3.1 engages cell cycle and cell death machinery via association with HDAC1, leading to increased p53 acetylation and half-life through MDM2-dependent mechanisms. Importantly, overexpression of Nkx3.1 has little effect on Pten wild-type epithelium, suggesting that PTEN plays a predominant role in PTEN-NKX3.1 interplay. Manipulating NKX3.1 expression may serve as a therapeutic strategy for treating PTEN-deficient prostate cancers.