|Year : 2019 | Volume
| Issue : 5 | Page : 989-993
Expression of androgen receptor in primary breast carcinoma and its relation with clinicopathologic features, estrogen, progesterone, and her-2 receptor status
Gnanapriya Vellaisamy, Rajalakshmi Tirumalae, YK Inchara
Department of Pathology, St. John's Medical College, Bengaluru, Karnataka, India
|Date of Web Publication||4-Oct-2019|
Department of Pathology, St. John's Medical College, Sarjapur Road, Bengaluru - 560 034, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: The role of estrogen/progesterone receptors (ER/PR) is well-established with respect to therapy and prognosis of breast carcinoma. However, the role of androgen receptor (AR) expression is unclear in the Indian context. The objective is to study the following: (a) Expression of AR in resection specimens of ductal carcinomas, (b) Relationship of AR with clinicopathologic features, ER, PR, and Her-2 status.
Materials and Methods: This study included female patients with infiltrating ductal carcinoma with a minimum of 10 axillary lymph nodes, whose hormone receptor status data were available. Demographic and histopathologic details were retrieved. Immunohistochemistry for AR was done and considered positive if ≥10% of tumor cells showed nuclear staining and compared to various clinicopathologic features.
Results: A total of 71 cases were included in the study. AR expression was noted in 52% of cases. Of the 35 ER and/or PR expressing tumors, AR was positive in 24 cases. In contrast, of the 36 ER/PR-negative tumors, AR was expressed in only 13 cases (P = 0.006). There was no significant difference in the expression of AR between Her-2 positive and negative cases. AR positivity was noted in 23% of triple-negative tumors. Age did not show an influence on AR status. Among histopathologic parameters, low-grade tumors were significantly associated with AR expression (P = 0.018) while tumor size, lymphovascular emboli, and nodal status were not. Within the follow-up period, four patients from AR-positive group developed distant metastasis.
Conclusion: Indian patients with breast carcinoma have a higher AR expression in low-grade and ER/PR-positive tumors, in concordance with Western studies. A good number of triple-negative tumors also express AR, which needs further evaluation.
Keywords: Androgen receptor, breast carcinoma, estrogen/progesterone receptor
|How to cite this article:|
Vellaisamy G, Tirumalae R, Inchara Y K. Expression of androgen receptor in primary breast carcinoma and its relation with clinicopathologic features, estrogen, progesterone, and her-2 receptor status. J Can Res Ther 2019;15:989-93
|How to cite this URL:|
Vellaisamy G, Tirumalae R, Inchara Y K. Expression of androgen receptor in primary breast carcinoma and its relation with clinicopathologic features, estrogen, progesterone, and her-2 receptor status. J Can Res Ther [serial online] 2019 [cited 2020 Feb 28];15:989-93. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/989/244222
| > Introduction|| |
The traditional prognostic and predictive markers of breast carcinoma include histological subtype, grade of the tumor, and clinical stage of the disease which is based on tumor size, lymph node status, and the presence or absence of distant metastasis. In the past two decades, biomarkers such as hormone receptors (estrogen/progesterone receptor [ER/PR]) and Her-2 growth factor receptor have gained importance due to implications in prognosis and clinical management. In spite of these, the outcome is difficult to predict in a subgroup of cancers which are ER-negative or triple negative and the search for new markers continues.
Androgen receptor (AR) is one such emerging biomarker. It belongs to the steroid hormone nuclear receptor family similar to ER and PR. The role of AR in development of prostate and progression of prostate cancer is well documented. However, its role in breast cancer is unclear. It has been hypothesized that androgens influence the development of breast cancer by its conversion to estradiol or by its binding to a subset of estrogen-responsive element or by its direct binding to AR. Thus, AR is thought to play a central role in its initiation, progression of breast cancer, and its response to therapy.
It had been previously documented in other studies that AR is highly expressed in breast cancer with an expression rates ranges between 60% and 80%.,,,, AR is often associated with lower grade of the tumor. In studies by Hu et al. and Agoff et al., AR expression and patients survival depend on the status of ER. Hence, there is a need to study the coexpression of these receptors to assess better prediction of patient's survival. There is limited literature from India, on role of AR in breast cancer.,, This study was undertaken to study the relationship of AR status with clinicopathological parameters and biomarkers. The objective was to study the following: (a) Expression of AR in resection specimens of ductal carcinomas, (b) Relationship of AR with clinicopathologic features, ER, PR, and Her-2 status
| > Materials and Methods|| |
This is a retrospective study approved by the Institutional Ethics Committee. The study included mastectomy/lumpectomy specimens of ductal carcinoma in female patients with known hormone receptor status (ER, PR, and Her2) and a minimum of 10 axillary lymph nodes. Patients with inadequate clinical data or unavailable slides and blocks were excluded from the study. A total of 71 patients were included in this study. Patient demographic details (age) and histopathological parameters such as tumor size, lymphovascular emboli (LVI), tumor infiltrating lymphocytes (TIL), grade of the tumor (Modified Bloom-Richardson grade), lymph node involvement, and hormone receptor status (ER, PR, and Her-2 receptor) were retrieved from the hospital information system and medical records.
Immunohistochemistry (IHC) for biomarker AR was performed using polymer technique on tissue sections of 4–5 μm thickness adhesive slides. The slides were incubated overnight at 60°C. Antigen retrieval was performed using pressure cooker method in citrate buffer. The slides were incubated with primary rabbit monoclonal antibody (clone EP120, Pathnsitu) at room temperature for 30 min. Subsequently, the slides were incubated with secondary antibody and immunoreactivity was detected using diaminobenzidine as chromogen. The slides were counterstained with Harris's hematoxylin. Prostate tissue was used as AR-positive controls. Tumors with ≥10% nuclear staining of neoplastic cells were considered as positive. For ER and PR tumor cells with at least 1% stained cells were considered as positive. Her-2 status was interpreted according to the American Society of Clinical Oncology/College of American Pathologists guideline recommendations. FISH was not done in borderline cases. A score of both 1+ and 2+ were considered as negative.
Statistical analysis was performed using Statistical Package for Social Sciences version 15.0 software (SPSS Inc, Chicago, IL). The Chi-square test was used to assess the association between clinicopathological variables and AR positivity. A value of P < 0.05 was considered as statistically significant.
| > Results|| |
AR expression was noted in 52% (37/71) of tumors in this cohort. The relationship between various clinicopathological parameters and biomarkers with AR expression is depicted in [Table 1]. The mean age at diagnosis was 51 ± 10 years. Thirty-four patients were above the age of 50 years. Although high AR expression (62%) was noted in patients aged above 50 years, it was not statistically significant. AR positivity was noted in 78%, 58%, and 26% of Grade I, II, and III tumors, respectively. Low-grade tumors had significantly higher AR expression with a P value of 0.018 [Figure 1]. Among the histopathologic parameters evaluated, grade of the tumors and TIL showed a significant AR expression but not with tumor size, LVI, and nodal status. Expression of AR was also noted either as scattered or clustered positivity in the luminal cells of terminal ductal-lobular unit (TDLU) of normal breast epithelium adjacent to the neoplasm [Figure 2].
|Table 1: Relationship of androgen receptor with clinicopathological parameters and hormonal receptor status|
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|Figure 1: Diffuse strong nuclear staining for androgen receptor (b) (Original magnification ×20) in well-differentiated ductal carcinomas (a) (H and E, Original magnification ×20) and negative staining for androgen receptor (d) (Original magnification ×20) in poorly differentiated ductal carcinomas (c) (H and E, Original magnification ×20)|
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|Figure 2: Positive nuclear staining for androgen receptor in luminal cells of terminal ductal-lobular unit (Original magnification × 40)|
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Expression of ER, PR, and Her-2 receptors was noted in 52% (n = 37), 46% (n = 33), and 14% (n = 10), respectively. AR was expressed in 73% of ER-positive tumors [Figure 3]. Among ER-negative tumors, AR was expressed in 29% of the tumors that belong to high grade (Grade II and III). AR expression showed a significant association with ER (P = 0.00) and PR positive tumors (P = 0.006). In Her-2 positive tumors, AR expression was seen in 70% of the tumors. In spite of higher percentage of AR positivity in Her-2 positive tumors, the P value was not statistically significant. A functional cross-talk between AR and Her-2 was documented in a subset of ER-negative tumors in previous studies. Hence, the relationship between AR and Her-2 expression was studied in ER-negative tumors. Although, the percentage of AR expression in Her-2 positive tumors was higher (57%) as compared to Her-2 negative tumors and it did not attain statistical significance (P = 0.07).
|Figure 3: Diffuse strong nuclear staining for androgen receptor (Original magnification ×20) in luminal A tumors (estrogen receptor positive (Original magnification ×20), progesterone receptor positive (Original magnification ×20), Her2-neu negative (Original magnification ×20)|
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Among luminal A, luminal B, Her-2 overexpression, and triple-negative cancers, the rates of AR expression were as follows: 69%, 100%, 57%, and 23%, respectively. Luminal A tumors had significantly higher AR expression (P = 0.006), whereas luminal B and Her-2 overexpression tumors did not. AR expression was significantly higher in nontriple negative tumors as compared to triple-negative tumors (P = 0.00).
The maximum duration of follow-up was 63 months for 37 patients. None of the patients died during the follow-up period. Hence, overall survival was not calculated. Four patients developed distant metastasis all of which were AR positive.
| > Discussion|| |
Breast cancer is the most common cancer in Indian women. The role of hormone receptors such as ER and PR in deciding the management and to assess the prognosis is well-established, but the significance of AR in breast cancer is still emerging. AR is highly expressed in breast cancer. The positive rates of expression of AR vary mostly from 60% to 80% in the literature.,,,, In this study, the expression rate was 52% which was almost similar as compared to the Western literature. An Indian study by Mishra et al. and a large study from Poland  reported lower rates of expression 40% and 43.4%, respectively, similar to this study. The varied rates of expression may be attributed due to the methodology used and the geographical distribution of the population studied.
Currently, it is thought that different types of luminal cells in the normal breast epithelium might serve as a precursor for different subtypes of cancer. AR is found to be expressed in luminal and metaplastic apocrine cells. The apocrine cells had shown a diffuse positivity with lack of expression of ER/PR, whereas the luminal cells of TDLU in the normal breast epithelium showed a scattered or clustered distribution for AR in a minority of cell population with a similar pattern as that of ER. Although AR has been expressed in the luminal cells, they are not biologically active. Wang reported an absence of downstream regulatory proteins (prostate-specific antigen, gross cystic disease fluid protein) in the normal breast epithelium by IHC. Further oncogenic events are essential for the initiation and the progression of breast cancer in these AR-positive luminal cells. Similar distribution pattern of AR is noted in the adjacent breast epithelium of this study.
The published data are inconsistent with respect to the relationship between the AR status and the various clinicopathological parameters. The most consistent parameter which correlated with AR status is the grade of the tumor. Park et al. have reported a higher AR expression in patients with smaller tumor size and lower histological grade, but not with age, body mass index, preoperative CEA levels, menopausal status, nodal involvement, and stage. Ogawa et al. reported its expression as a favorable marker in relation to lower grade, smaller size, scirrhous type tumors, and the absence of lymph node metastasis. A study by Agrawal et al., found a relation with only tumor grade. Similar to other studies, we found significantly higher AR expression in patients with low-grade tumors. Similarly, TIL also showed a significant association with AR expression. The rest of the parameters such as age, tumor size, nodal status, and LVI did not show any association.
The frequency of AR expression is generally comparable with or higher than that of ER/PR expression. In this study, the expression rates of both AR and ER were the same. AR expression showed a relation with ER and PR expression but not with Her-2 expression, as reported by previous studies. AR was expressed in 29% of ER-negative tumors that belong to high grade. ER-negative and AR-positive tumors were previously called as molecular apocrine tumors (which exhibits histological evidence of apocrine differentiation). In this group of tumors, AR signaling was intact and active. Overexpression of AR and ErbB2 was revealed in 50% of ER-negative tumors by gene expression studies. A functional cross-talk existed between ER and ErbB2 in this subgroup of tumors. In ER-negative tumors, the percentage of AR expression is higher in Her-2 positive tumors but not statistically significant. This may be due to less number of Her-2 positive tumors. Niemeier et al. had also reported increased expression of AR in Her-2 tumors of ER-negative subgroup.
ER, PR, and Her-2 have been considered as immunohistochemical surrogate markers for molecular subtypes of cancer. AR expression is higher in luminal A tumors but not with other subtypes. In triple-negative tumors, the rates of AR expression varied from 6.6% to 75%. In this study, a significant proportion of triple-negative tumors (23%) expressed AR. Based on gene expression profiling; Lehman et al. subclassified triple-negative cancers into six distinct subtypes. Luminal AR subtype had the highest AR expression. As the patients with triple negative subset of tumors hardly gain any benefit from endocrine therapy, potential benefits of targeted therapy with AR needs to be evaluated. Thus, in addition to routine biomarkers (ER, PR, and Her-2), AR may be considered as a beneficial biomarker.
Four patients from AR-positive group developed distant metastasis during the follow-up period. AR expression influences distant metastasis is questionable. It is difficult to infer from such a small sample size with short follow-up period.
The strength of this study is that it has been done in a group of patients, where the clinicopathological data regarding the role of AR is sparse. The limitations are as follows: (1) small sample size, 2) AR expression is not correlated with overall survival and disease-free survival data, which may add information regarding the prognostic point of view.
| > Conclusion|| |
Low-grade and ER/PR-positive tumors showed a significantly higher percentage of AR expression. AR was expressed in a higher percentage of Her2-positive tumors in ER-negative subset and in triple-negative tumors. The significance of these findings needs to be validated in a larger cohort.
The authors would like to thank St. John's Research Society
Financial support and sponsorship
This study was financially supported by St. John's Research Society.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Peters KM, Edwards SL, Nair SS, French JD, Bailey PJ, Salkield K, et al.
Androgen receptor expression predicts breast cancer survival: The role of genetic and epigenetic events. BMC Cancer 2012;12:132.
Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, et al.
Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res 2011;17:1867-74.
Moinfar F, Okcu M, Tsybrovskyy O, Regitnig P, Lax SF, Weybora W, et al.
Androgen receptors frequently are expressed in breast carcinomas: Potential relevance to new therapeutic strategies. Cancer 2003;98:703-11.
Gonzalez LO, Corte MD, Vazquez J, Junquera S, Sanchez R, Alvarez AC, et al.
Androgen receptor expresion in breast cancer: Relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors. BMC Cancer 2008;8:149.
Isola JJ. Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol 1993;170:31-5.
Kuenen-Boumeester V, Van der Kwast TH, van Putten WL, Claassen C, van Ooijen B, Henzen-Logmans SC, et al.
Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer. Int J Cancer 1992;52:581-4.
Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ. Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical, and prognostic associations. Am J Clin Pathol 2003;120:725-31.
Mishra AK, Agrawal U, Negi S, Bansal A, Mohil R, Chintamani C, et al.
Expression of androgen receptor in breast cancer & its correlation with other steroid receptors and growth factors. Indian J Med Res 2012;135:843-52.
] [Full text]
Chintamani, Kulshreshtha P, Chakraborty A, Singh L, Mishra AK, Bhatnagar D, et al.
Androgen receptor status predicts response to chemotherapy, not risk of breast cancer in Indian women. World J Surg Oncol 2010;8:64.
Rajender S, Francis A, Pooja S, Krupakar N, Surekha D, Reddy G, et al.
CAG repeat length polymorphism in the androgen receptor gene and breast cancer risk: Data on Indian women and survey from the world. Breast Cancer Res Treat 2011;127:751-60.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al.
Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol 2013;31:3997-4013.
Naderi A, Hughes-Davies L. A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia 2008;10:542-8.
Agrawal AK, Jeleń M, Grzebieniak Z, Zukrowski P, Rudnicki J, Nienartowicz E, et al.
Androgen receptors as a prognostic and predictive factor in breast cancer. Folia Histochem Cytobiol 2008;46:269-76.
Bratthauer GL, Lininger RA, Man YG, Tavassoli FA. Androgen and estrogen receptor mRNA status in apocrine carcinomas. Diagn Mol Pathol 2002;11:113-8.
Wang X. Androgen receptor (AR) and breast cancer: Reference to the AR status in normal/benign breast luminal cells. Receptors Clin Investig 2015;2:e533.
Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH, et al.
Expression of androgen receptors in primary breast cancer. Ann Oncol 2010;21:488-92.
Ogawa Y, Hai E, Matsumoto K, Ikeda K, Tokunaga S, Nagahara H, et al.
Androgen receptor expression in breast cancer: Relationship with clinicopathological factors and biomarkers. Int J Clin Oncol 2008;13:431-5.
Agrawal A, Ziolkowski P, Grzebieniak Z, Jelen M, Bobinski P, Agrawal S, et al.
Expression of androgen receptor in estrogen receptor-positive breast cancer. Appl Immunohistochem Mol Morphol 2016;24:550-5.
Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, et al.
An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 2006;25:3994-4008.
Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, Larsimont D, et al.
Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 2005;24:4660-71.
Chia KM, Liu J, Francis GD, Naderi A. A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia 2011;13:154-66.
Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: Expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol 2010;23:205-12.
Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, et al.
Breast cancer subtypes and response to docetaxel in node-positive breast cancer: Use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 2009;27:1168-76.
Rampurwala M, Wisinski KB, O'Regan R. Role of the androgen receptor in triple-negative breast cancer. Clin Adv Hematol Oncol 2016;14:186-93.
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al.
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011;121:2750-67.
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