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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 76-79

Androgen receptor in breast cancer: A tissue microarray-based study


Department of Pathology, Kempegowda Institute of Medical Sciences, Bengaluru, Karnataka, India

Date of Submission06-Jan-2021
Date of Decision24-Jan-2021
Date of Acceptance27-Jan-2021
Date of Web Publication26-Jun-2021

Correspondence Address:
Dr. Savithri Ravindra
Department of Pathology, Kempegowda Institute of Medical Sciences, Bengaluru - 560 070, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_5_21

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  Abstract 


Background and Aim: Breast carcinoma is the most common malignant tumor and the leading cause of cancer deaths in women. The incidence of breast cancer in India has been gradually raising accounting for 25%–33% of all cancers in women. Breast carcinomas are a heterogeneous group of tumors which show varied behavior and response to therapeutic agents. Androgen receptors (ARs) have been studied in great detail in prostate cancers, now being studied in breast cancers, but its role in breast cancer has not been elucidated completely. The aim of our study was to evaluate the expression of AR in invasive carcinoma of the breast and to evaluate its relation to estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal growth factor Receptor2 (HER2) expression on tissue microarray (TMA) sections. Materials and Methods: This was a descriptive study which included 53 cases of breast carcinoma. The specimens were fixed in 10% formalin, routinely processed. A master block for TMA was made by taking 2 mm cores from paraffin blocks containing tumor. Sections were taken and stained for ER, PR, AR, and HER2. Results: A total of 53 cases were studied. Around 63% of breast carcinomas were positive for AR. Conclusion: AR expression can be used as an additional biomarker in breast carcinomas, and a large number of cases can be studied by TMA sections.

Keywords: Androgen receptor, breast carcinoma, hormone receptors, tissue microarray


How to cite this article:
Chavan S, Ravindra S. Androgen receptor in breast cancer: A tissue microarray-based study. Arch Med Health Sci 2021;9:76-9

How to cite this URL:
Chavan S, Ravindra S. Androgen receptor in breast cancer: A tissue microarray-based study. Arch Med Health Sci [serial online] 2021 [cited 2021 Dec 8];9:76-9. Available from: https://www.amhsjournal.org/text.asp?2021/9/1/76/319400




  Introduction Top


Breast carcinoma is the most common malignant tumor and the leading cause of cancer deaths in women. The incidence of breast cancer in India has been gradually raising accounting for 25%–33% of all cancers in women.[1]

Breast carcinomas are a heterogeneous group of tumors which show varied behavior and response to therapeutic agents.[2] With recent advances in molecular biology, new markers with prognostic significance are being discovered which can alter treatment modality.

Androgen receptors (ARs) have been studied in great detail in prostate cancers, now being studied in breast cancers, but its role in breast cancer has not been elucidated completely.

The most common method is immunohistochemical analysis on whole sections or on tissue microarray (TMA). TMA is a novel technology which allows us to evaluate different markers and derive its relation to a tumor. In this study, we analyzed the role of AR in breast carcinoma using TMA sections.

AR is expressed in many types of breast carcinoma, including both invasive and in situ ductal carcinomas, lobular carcinoma, BReast CAncer gene (BRCA)-mutated tumors, and mammary Paget's disease. Its expression is correlated with a better prognosis for breast carcinoma. The aim of our study was to evaluate the expression of AR in invasive carcinoma of the breast and to evaluate its relation to estrogen receptor (ER), progesterone receptor (PR), and HER2 expression on TMA sections.


  Materials and Methods Top


Fifty-three cases of breast carcinoma were included in the study.

The mastectomy or lumpectomy specimens were fixed in 10% formalin for about 24 h, routinely processed, sectioned, and stained with H and E stain. These sections were studied in detail for grading, typing, and lymph node involvement

One paraffin block from tumor is selected in all cases. An area in the block is marked for taking core by matching with the microscopic areas of tumor.

Master block of TMA was constructed by taking a single 2 mm core from each block with the help of a manual TMA set (Quick Ray manual tissue microarrayer, Ultima Co., Korea).

Meanwhile, using Microsoft Excel sheet, a grid was prepared on the computer indicating the position of each case.

The first column of the first row on the top left and the last three columns of the last row at the bottom right were left blank for easy orientation of the sections when cut.

Sections were taken on regular glass slide for H and E and on polylysine slide for immunohistochemistry (IHC).

Immunostaining for ER, PR, and AR on TMA sections was performed using ER-alpha, Clone EP1 (Monoclonal, DAKO), PR, Clone PgR 636 (Monoclonal, DAKO), AR antibody (Polyclonal, DAKO), and HER2 staining done (Polyclonal, DAKO).

ER and PR were scored using H-score method, for HER2 3 + staining was taken as positive. AR was considered positive if 10% of the tumor cells showed nuclear staining [Figure 1].
Figure 1: Tumor cells showing androgen receptor positivity (×40)

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  Results Top


Of the 53 cases of breast carcinoma included in the TMA study, 36 were available for AR analysis, as 17 cores floated during IHC staining.

These 36 cases included 33 infiltrating duct carcinomas, one case each of apocrine, mucinous, and metaplastic carcinomas.

Among 33 cases of infiltrating ductal carcinoma (IDC), 21 (63.6%) were AR positive [Figure 1] and [Figure 2].
Figure 2: Tumor cells showing androgen receptor positive (×100)

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Both mucinous and metaplastic carcinomas showed AR positivity, and the apocrine carcinoma was negative [Figure 3].
Figure 3: Tumor cells androgen receptor negative (×100)

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Relation between androgen receptor expression and clinicopathological factors

Androgen receptor and histological type

Out of available 36 cores, 33 were IDC, 1 case each of apocrine, mucinous, and metaplastic carcinoma. Twenty-three of 36 were positive for AR.

Of the 33 IDCs, 21 (63.6%) were AR +ve. The apocrine carcinoma was AR −ve (ER, PR, and HER2 −ve), the mucinous carcinoma was AR +ve (ER, PR, and HER2 −ve). The metaplastic carcinoma was AR +ve (ER, PR, and HER2 −ve).

AR expression was higher in tumors >5 cm size (7/8, 87.5%) [Table 1].
Table 1: Androgen receptors and size of tumor

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The 33 IDCs were graded by modified Bloom and Richardson grading, and AR expression did not vary much with the tumor grade [Table 2].
Table 2: Androgen receptors and grade of tumor

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Of the 36 cases, 32 showed metastases to lymph nodes, and in that, 16 (50%) were AR positive.

We noted of the 28 cases of ER PR positives, 18 showed AR positivity, and among 8 ER-negative cases, 5 were positive for AR. AR was positive in many HER2-negative cases [Table 3].
Table 3: Androgen receptors and other receptors

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  Discussion Top


Breast carcinoma is the most common malignant tumor and the leading cause of cancer deaths in women. The incidence of breast cancer in India has been gradually raising accounting for 25%–33% of all cancers in women.[1]

Breast carcinomas are a heterogeneous group of tumors which show varied behavior and response to therapeutic agents.[2] With recent advances in molecular biology, new markers with prognostic significance are being discovered which can alter treatment modality.

TMA is a novel technology which allows us to evaluate different markers and derive its relation to a tumor. In this study, we analyzed ARs in breast carcinoma using TMA sections.

ARs have been studied in great detail in prostate cancers, but its role in breast cancer has not been elucidated completely. AR plays a significant role in breast development. While most studies have demonstrated that AR has antiproliferative activity, few studies have shown that AR induces ductal proliferation.

Fioretti et al.[3] in their review quote many studies that demonstrated that AR signaling is inhibitory toward breast carcinoma cell line growth.[4],[5],[6],[7],[8] However, some studies have observed that androgens have a pro-proliferative activity.[9],[10],[11] The disparity between these studies is yet to be resolved.

AR is known to be expressed in luminal cells. Wang reported in the normal breast epithelium the absence of downstream regulator proteins by IHC.[12]

AR is expressed in many types of breast carcinoma, including both invasive and in situ ductal carcinomas, lobular carcinoma, BRCA-mutated tumors, and mammary Paget's disease. Its expression is correlated with a better prognosis for breast carcinoma.[13]

Many observers found AR expression in >70% of breast carcinoma.

Niemeier et al. noted positivity in 80% of their cases.[14] In a study from Poland, they observed much lower expression of AR along with ER and PR expression.[15]

Collins et al., in their large population-based study, which included 3093 cases of breast cancer, noted AR expression in luminal A and B types of invasive breast cancer and in a subset of HER2-type and basal-like cancers. They made TMA blocks and sections for 3093 breast cancer cases and found 77% cases as AR positive.[16]

A study from China with 980 breast carcinoma cases noted 77% AR positivity and concluded that more breast carcinomas express AR than ER and PR. In good number of ER-negative patients, AR could serve as a potential therapeutic target.[17]

We observed AR positivity in 64% of ductal carcinomas. A recent study from southern India also observed 52% AR positivity.[18]

One each of metaplastic and mucinous carcinomas was AR positive, but the apocrine carcinoma was negative.

Many authors demonstrated AR positivity in the tumors with apocrine differentiation. We noted AR-negative status in the single apocrine carcinoma.

Park et al. noted AR expression in 35% of triple-negative cancers, whereas metaplastic, medullary, and mucinous carcinomas showed less expression.[19] We noted AR positivity in both mucinous and metaplastic carcinomas. In a study from Yale University, they found 36% AR expression among the 50 triple-negative carcinomas and suggested the need for routine assessment of AR in at least all triple-negative breast cancers and apocrine carcinomas as a potential target for therapy.[20]

Yiğit et al. in their study of seven adenoid cystic carcinomas observed AR expression in majority of them.[21]

AR expression was seen equally in all grades of tumor in contrast to other studies that observed positivity in low-grade tumors.[14],[18]

AR expression did not correlate with lymph node status similar to other studies.[18] Most of the HER2-negative tumors showed AR expression. More studies are being done to evaluate the effect of targeted therapy, and it may be beneficial in triple-negative patients.

Limitations

There were certain limitations in this study. AR expression was studied on TMA sections only and not on whole sections, hence minor variations may be there, and of the 53 cases, only 36 were available for study as 17 cores floated during staining. This can be overcome by duplication of the cores and taking precautions during staining.


  Conclusion Top


AR expression can be used as an additional biomarker in breast carcinomas, and a large number of cases can be studied by TMA sections.

Acknowledgment

The authors would like to thank Dr. Jyothi S Prabhu, Division of Molecular Medicine, St. John's Research Institute, Bangalore, India, for her guidance and support and also Dr. MSN Prasad, Consultant Pathologist, Bangalore Hospital, for his kind support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Khokhar A. Breast cancer in India: Where do we stand and where do we go? Asian Pac J Cancer Prev 2012;13:4861-6.  Back to cited text no. 1
    
2.
Rivenbark AG, O'Connor SM, Coleman WB. Molecular and cellular heterogeneity in breast cancer – Challenges for personalized medicine. Am J Clin Pathol 2013;183:1113-24.  Back to cited text no. 2
    
3.
Fioretti FM, Sita-Lumsden A, Bevan CL, Brooke GN. Revising the role of the androgen receptor in breast cancer. J Mol Endocrinol 2014;52:R257-65.  Back to cited text no. 3
    
4.
Zhou J, Ng S, Adesanya-Famuiya O, Anderson K, Bondy CA. Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J 2000;14:1725-30.  Back to cited text no. 4
    
5.
Ortmann J, Prifti S, Bohlmann MK, Rehberger-Schneider S, Strowitzki T, Rabe T. Testosterone and 5α-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines. Gynecol Endocrinol 2002;16:113-20.  Back to cited text no. 5
    
6.
Dimitrakakis C, Zhou J, Wang J, Belanger A, LaBrie F, Cheng C, et al. A physiologic role for testosterone in limiting estrogenic stimulation of the breast. Menopause 2003;10:292-8.  Back to cited text no. 6
    
7.
Macedo LF, Guo Z, Tilghman SL, Sabnis GJ, Qiu Y, Brodie A. Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res 2006;66:7775-82.  Back to cited text no. 7
    
8.
Cops EJ, Bianco-Miotto T, Moore NL, Clarke CL, Birrell SN, Butler LM, et al. Antiproliferative actions of the synthetic androgen, mibolerone, in breast cancer cells are mediated by both androgen and progesterone receptors. J Steroid Biochem Mol Biol 2008;110:236-43.  Back to cited text no. 8
    
9.
Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ, et al. Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol 1995;52:459-67.  Back to cited text no. 9
    
10.
Maggiolini M, Donzé O, Jeannin E, Andò S, Picard D. Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor α. Cancer Res 1999;59:4864-9.  Back to cited text no. 10
    
11.
Lin HY, Sun M, Lin C, Tang HY, London D, Shih A, et al. Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-α-positive and -negative breast cancer cells. J Steroid Biochem Mol Biol 2009;113:182-8.  Back to cited text no. 11
    
12.
Wang X. Androgen receptor (AR) and breast cancer: Reference to AR status in normal benign breast luminal cells. Receptors Clin Investing 2015;2:e533.  Back to cited text no. 12
    
13.
Iacopetta D, Rechoum Y, Fuqua SA. The role of androgen receptor in breast cancer. Drug Discov Today Dis Mech 2012;9:e19-7.  Back to cited text no. 13
    
14.
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.  Back to cited text no. 14
    
15.
Agrawal AK, Jeleń M, Grzebieniak Z, Zukrowski P, Rudnicki J, Nienartowicz E. Androgen receptors as a prognostic and predictive factor in breast cancer. Folia Histochem Cytobiol 2008;46:269-76.  Back to cited text no. 15
    
16.
Collins LC, Cole K, Marotti J, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: Results from the nurses' health study. Mod Pathol 2011;24:924-31.  Back to cited text no. 16
    
17.
Qi JP, Yang YL, Zhu H, Wang J, Jia Y, Liu N, et al. Expression of the androgen receptor and its correlation with molecular subtypes in 980 Chinese breast cancer patients. Breast Cancer: Basic and Clinical Research 2012;6:1-8.  Back to cited text no. 17
    
18.
Vellaisamy G, Tirumalae R, Inchara YK. Expression of androgen receptor in primary breast carcinoma and its relation with clinicopathologic features, estrogen, progesterone, and her-2 receptor status. J Cancer Res Ther 2019;15:989-93.  Back to cited text no. 18
    
19.
Park S, Koo J, Park HS, Choi SY, Lee JH, Park BW, et al. Expression of androgen receptors in primary breast cancer. Ann Oncol 2010;21:488-92.  Back to cited text no. 19
    
20.
Safarpour D, Pakneshan S, Tavassoli FA. Androgen receptor (AR) expression in 400 breast carcinomas: Is routine AR assessment justified? Am J Cancer Res 2014;4:353-68.  Back to cited text no. 20
    
21.
Yiğit S, Etit D, Hayrullah L, Atahan MK. Androgen receptor expression in adenoid cystic carcinoma of breast: A subset of seven cases. Eur J Breast Health 2020;16:44-7.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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