Lack 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.
ABSTRACT Androgen receptor has been implicated in the pathogenesis of breast carcinoma. In this study, we explored the potential role of androgen receptor in breast cancer by analyzing its expression using immunohistochemistry and its relationship with tumor progress (ductal carcinoma in situ [DCIS] versus invasive ductal carcinoma [IDC]); nuclear grades (high grade [HG] versus non-high grade); expression of estrogen receptor (ER), progesterone receptor (PR), HER-2; and 3 molecular classifications: cytokeratin classification, triple (ER/PR/HER-2) negative classification, and ER/HER-2 classification in 184 breast carcinomas. We found that (1) lack of androgen receptor expression was associated with HG-IDC and with basal subtypes of HG-IDC, suggesting androgen receptor may play an important role in preventing the invasive transformation in this subgroup of breast carcinoma. (2) HG-IDC and HG-DCIS more frequently expressed androgen receptor than ER (55%-93% for androgen receptor and 18%-30% for ER) and were frequently androgen receptor+/ER- (63% for HG-DCIS and 39% for HG-IDC), which made androgen receptor a possible therapeutic target. (3) One third of HG-IDC was negative for androgen receptor, ER, PR, and HER-2, suggesting that further studies are needed to identify other key molecules for targeted therapy. We purpose that androgen receptor should be routinely measured for breast cancer.
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ABSTRACT: Mammary Paget's disease and extramammary Paget's disease are rare intraepithelial neoplasms. Mammary Paget's disease is almost exclusively associated with underlying invasive breast carcinoma or high-grade ductal carcinoma in situ (DCIS G3). Extramammary Paget's disease arises in areas rich in apocrine glands and is suspected to have apocrine gland origin. The aim of the study was to investigate the presence of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and Her2/neu in a large number of cases. We investigated 58 cases of mammary and 23 cases of extramammary Paget's disease. Formalin-fixed and paraffin-embedded tissues were analyzed using antibodies against AR, PR, ER and Her2/neu according to standardized procedures. In mammary Paget's disease, positive immunoreactions for Her2/neu, AR and ER were observed in 56 of 58 (97%), 51 of 58 (88%), and respectively in six of 58 (10%) cases. All cases of mammary Paget's disease were negative for PR and showed a coexpression of Her2/neu and AR in 51 out of 58 cases (88%). In extramammary Paget's disease, positive immunoreactions for AR, Her2/neu and ER were observed in 18 of 23 (78%), 12 of 23 (52%), and respectively in 1 of 23 (4%) cases. All cases of extramammary Paget's disease were negative for PR and showed a coexpression of AR and Her2/neu in 12 out of 23 cases (52%). In contrast to ER and PR, AR and Her2/neu are commonly expressed in mammary and extramammary Paget's disease. The knowledge about frequent expression of AR in Paget's disease could lead to the development of a new adjuvant therapy, particularly in patients with recurrent disease.Modern Pathology 11/2005; 18(10):1283-8. · 5.25 Impact Factor
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ABSTRACT: Previous in vitro studies demonstrated that bioactive androgen 5alpha-dihydrotestosterone (DHT) exerted antiproliferative effects through an interaction with androgen receptor (AR) in breast carcinoma cells. However, AR status has not been examined in association with DHT concentration in breast carcinoma tissues, and significance of androgenic actions remains unclear in breast carcinomas. Therefore, in our study, we first examined intratumoral DHT concentrations in 38 breast carcinoma tissues using liquid chromatography/electrospray tandem mass spectrometry. Intratumoral DHT concentration was positively associated with 5alpha-reductase type 1 (5alphaRed1), and negatively correlated with aromatase. We then examined clinical significance of AR and 5alphaRed1 status in 115 breast carcinoma tissues by immunohistochemistry. Breast carcinomas positive for both AR and 5alphaRed1 were inversely associated with tumor size or Ki-67. These patients showed significant associations with a decreased risk of recurrence and improved prognosis for overall survival, and the AR / 5alphaRed1 status was demonstrated an independent prognostic factor. Moreover, we examined possible regulation of DHT production by aromatase in in vitro studies. DHT synthesis from androstenedione in MCF-7 cells was significantly inhibited by coculture with aromatase-positive stromal cells, which was significantly reversed by addition of aromatase inhibitor exemestane. These results suggest that intratumoral DHT concentration is mainly determined by 5alphaRed1 and aromatase in breast carcinoma tissues, and antiproliferative effect of DHT may primarily occur in the cases positive for both AR and 5alphaRed1. Aromatase inhibitors may be more effective in these patients, possibly due to increasing local DHT concentration with estrogen deprivation.International Journal of Cancer 02/2007; 120(2):285-91. · 6.20 Impact Factor
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ABSTRACT: The role of androgens in breast cancer etiology has been unclear. Epidemiologic studies suggest that endogenous testosterone levels are positively associated with breast cancer risk in postmenopausal women. Given the increasing trend in the use of hormone therapies containing androgens, we evaluated the relation between the use of estrogen and testosterone therapies and breast cancer. We conducted a prospective cohort study in the Nurses' Health Study from 1978 to 2002 to assess the risk of breast cancer associated with different types of postmenopausal hormone (PMH) formulations containing testosterone. During 24 years of follow-up (1 359 323 person-years), 4610 incident cases of invasive breast cancer were identified among postmenopausal women. Information on menopausal status, PMH use, and breast cancer diagnosis was updated every 2 years through questionnaires. Among women with a natural menopause, the risk of breast cancer was nearly 2.5-fold greater among current users of estrogen plus testosterone therapies (multivariate relative risk, 2.48; 95% confidence interval, 1.53-4.04) than among never users of PMHs. This analysis showed that risk of breast cancer associated with current use of estrogen and testosterone therapy was significantly greater compared with estrogen-only therapy (P for heterogeneity, .007) and marginally greater than estrogen and progesterone therapy (P for heterogeneity, .11). Women receiving PMHs with testosterone had a 17.2% (95% confidence interval, 6.7%-28.7%) increased risk of breast cancer per year of use. Consistent with the elevation in risk for endogenous testosterone levels, women using estrogen and testosterone therapies have a significantly increased risk of invasive breast cancer.Archives of Internal Medicine 08/2006; 166(14):1483-9. · 11.46 Impact Factor