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World J Surg Oncol
World J Surg Oncol
World Journal of Surgical Oncology
1477-7819
BioMed Central London

39256855
3525
10.1186/s12957-024-03525-z
Research
Androgen receptor expression and clinical characteristics in breast cancer
Wang Dan-dan 1
Jiang Lin-hong 2
Zhang Jian 1
Chen Xiu 1
Zhou Hong-lei 1
Zhong Shan-liang slzhong@njmu.edu.cn

3
Zhang He-da zhanghedazhd@163.com

1
1 https://ror.org/04py1g812 grid.412676.0 0000 0004 1799 0784 Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Jiangsu, 210029 P. R China
2 https://ror.org/04py1g812 grid.412676.0 0000 0004 1799 0784 Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu China
3 https://ror.org/03108sf43 grid.452509.f 0000 0004 1764 4566 Center of Clinical Laboratory Science, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, 42 Baiziting, Jiangsu, 210029 P. R China
11 9 2024
11 9 2024
2024
22 24329 4 2024
1 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Objective

To investigate the relationship between the expression of androgen receptor (AR) and clinical characteristics in breast cancer.

Patients and methods

The clinical records of all 432 patients tested for AR in our institution between January 2020 and May 2023 were reviewed. Clinical characteristics, age, menopausal status, tumor node metastasis (TNM) stage, distant metastasis, pathological complete response (pCR), histopathological features histological grade, estrogen receptor (ER), progesterone receptor, Her-2, Ki-67, and molecular subtype were registered for all patients.

Results

About 377 (87.27%) of the 432 patients had AR expression.

No significant difference in AR expression was found with age, menopausal status, TNM stage of primary tumor, or pCR. AR was positively and significantly associated with the histological grade, and recurrence. The AR expression was significantly related with molecular subtypes, including ER, PR Her-2, Ki67 and molecular subtype. ER (OR = 10.489, 95%CI: 5.470–21.569), PR (OR = 7.690, 95%CI: 3.974–16.129, Her-2 (OR = 10.489, 95%CI: 2.779–23.490 and tumor recurrence (OR = 0.110, 95%CI: 0.031–0.377 were significant independent risk factors affecting AR expression.

Conclusions

AR expression can serve as a reliable basis for judging the clinical molecular types and poor prognosis for breast cancer. AR may be a novel biomarker and target in AR-positive breast cancer depending on significant difference in AR expression among different molecular types of breast cancer.

Keywords

Breast cancer
Androgen receptor
Estrogen receptor
Clinical characteristics
National Natural Science Foundation of China82303449 82102780 Wang Dan-dan Zhang He-da issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Breast cancer is the most common malignancy and the first leading cause of cancer-related death in women worldwide. It is highly heterogeneous at molecular and clinical levels [1]. The main breast cancer subtypes include luminal A, Luminal B, Her-2-enriched and basal-like type, and normal-like type, depending on molecular profiles and several biomarkers [2]. Estrogen receptor (ER) and progesterone receptor (PR) as sex steroid hormone receptors are important biological markers for prognosis prediction in breast cancer. Androgen receptor (AR), another sex steroid hormone receptor family, is expressed in 70%-90% of breast cancer patients. The AR expression varies among breast cancer subtypes, and accounts for a large proportion in ER-positive tumors [3]. AR is a ligand-activated transcription factor. Increasing research shows AR played a dominant role in the development of breast cancer. AR can reportedly accelerate cell proliferation of ER-negative breast cancer and triple-negative breast cancer (TNBC) [4–6]. The main reason is that AR competes with ER for binding to androgen-responsive elements, leading to tumor cell growth [2]. The synergy between Her-2 and AR is reinforced by a positive feedback loop mechanism, which promotes Her-2 transcriptional upregulation and then activates related downstream pathways, accelerating AR-positive tumor growth [3, 7]. Additionally, AR promotes tamoxifen resistance probably by regulating cyclin D1 expression and promoting cell cycle progression [8]. However, some studies show serum androgen is positively associated with breast cancer risk whether in premenopausal or postmenopausal women [9–12]. Moreover, high AR expression is correlated with better disease-free survival (DFS) and overall survival (OS) [13]. Therefore, the existing views concerning the prognostic value of AR in different breast cancer subtypes are controversial.

Although some research shows AR-target drugs are effective for AR-positive breast cancer, the patients who exactly benefit from AR-target therapies remain uncertain. The aim of this study was to investigate the clinical characteristics of AR in breast cancer, and to evaluate the prognostic value and provide a therapeutic tool for breast cancer.

Patients and methods

Totally 432 breast cancer patients receiving surgical resection at the First Affiliated Hospital of Nanjing Medical University between January 2020 and May 2023 were enrolled This study was approved by Ethics Committee of the Hospital (Ethics code 2022-SR-473).

Immunohistochemistry(IHC)

For IHC assay, the breast cancer tissue slides were incubated with the indicated primary antibodies (anti-AR, Clone number: EP120; ZSGB-BIO) overnight at 4℃. And then chromogenic detection was performed through a DBA detection kit (Kit-2031, Maixin, China). Data were obtained and analyzed by two experienced doctors of the pathology department of our hospital. and AR scores were presented as levels (0, none; 1 + , weak; 2 + , moderate; 3 + , strong) and the percentage of stained nuclei and divided into five groups (0: < 5%; 1:6%-25%; 2:26%-50%; 3:51%-75%; and 4–75%). Finally, the score was expressed as (staining intensity × percentage of positively stained cells).

Criteria for pathological results

The ER/PR status criterion is that ≥ 1% stained tumor nucleus is positive. The Her-2 status criteriona is that immunohistochemistry (IHC) confirms 3 + or 2 + (Fish confirm IHC) is positive. Ki67 is expressed in positive cells to calculate the percentage [14]. The 8th edition of Breast cancer TNM Staging Atlas from the American Joint Committee on Cancer (AJCC).

Statistical analysis

Statistical analysis was performed on SPSS 22.0. Associations between AR expression and clinicopathological features were assessed using Chi-square or Student's t-test and analysis of variance (ANOVA). Significant risk factors were used to predict AR expression using a multivariate logistic regression model. p < 0.05 was deemed as significant.

Results

AR expression in breast cancer tissue specimens

Of the 432 cases of ranged from 23 to 81 years (52.15 ± 11.10). Fifty five (12.7%) of the 432 patients were AR-negative and 377 (87.3%) patients were AR-positive (Table 1). Table 1 Clinical characteristics of breast cancer patients according to AR status

Variable	Patients	AR + (%)	AR-(%)	χ2	p	
Age	
  ≤ 50	184	154(83.7%)	30(16.3%)	3.6825	0.05499	
  > 50	248	223(89.92%)	25(10.08%)			
Menopausal status	
 Premenopausal	195	167(85.64%)	28(14.36%)	0.84737	0.3573	
 Postmenopausal	237	210(88.61%)	27(11.39%)			
T stage of primary tumor	
 T1	178	159(89.33%)	19(10.67%)	3.5689	0.3119	
 T2	213	185(86.85%)	28(13.15%)			
 T3	25	19(76%)	6(24%)			
 T4	16	14(87.5%)	2(12.5%)			
N of primary tumor	
 N0	210	182(86.67%)	28(13.33%)	1.257	0.7394	
 N1	152	135(88.82%)	17(11.18%)			
 N2	43	38(88.37%)	5(11.63%)			
 N3	27	22(81.48%)	5(18.52%)			
Distant Metastases	
 Metastases	3	2(66.67%)	1(33.33%)	1.154	0.2827	
 None	429	375(87.41%)	54(12.59%)			
Stage	
 I	111	98(88.29%)	13(11.71%)	1.7648	0.94	
 IIA	149	130(87.25%)	19(12.75%)			
 IIB	83	73(87.95%)	10(12.05%)			
 IIIA	51	43 (84.31%)	8(15.69%)			
 IIIB	10	9(90%)	1(10%)			
 IIIC	25	22(88%)	3(12%)			
 IV	3	2(66.67%)	1(33.33%)			
pCR	
 pCR	14	10(71.43%)	4(28.57%)	0.44303	0.5057	
 non-PCR	73	58(79.45%)	15(20.55%)			
Histological grade	
 G1	4	4(100%)	0	13.197	0.00136	
 G2	163	155(95.09%)	8(4.91%)			
 G3	229	191(83.41%)	38(16.59%)			
Recurrence	
 No	421	372(88.36%)	49(11.64%)	17.762	2.503e-05	
 YES	11	5(45.45%)	6(54.55%)			

Relationship between AR expression and clinical features

Overall, 87 patients received neoadjuvant chemotherapy, among which 14 patients showed pathological complete response (pCR) (10 AR+ patients, 4 AR patients), and 73 patients were non-pCR (58 AR+ patients, 15 AR patients). In our series, AR expression was not significant in pCR (p = 0.5057, Table 1). Furthermore, no significant correlations were observed between AR expression and age, menopausal status, tumor size, lymph node, distant metastasis or tumor stage (Table 1).

In addition, 11 patients relapsed during follow-up. Our series showed a significant difference in AR expression and poor prognosis (p = 2.503e-05, Table 1). According to histological grade, there were significant differences in AR expression (p = 0.001363, Table 1).

Relationship between AR expression and molecular typing of breast cancer tissues

In all patients, 206 (47.7%) patients belonged to Luminal type, 83 (19.2%) patients were HR+/Her-2+, 54 (12.5%) patients were HR-/Her2+, and 82 (19.0%) patients were TNBC (Table 2). AR expression was related to the presence of ER (p=5.357e-15), PR (p=9.594e-11) and Her-2 (p= 8.408e-05). AR expression was also significantly associated with Ki-67 (p= 0.0458) and histological subtype (p<2.2e-16) (Table 2). Table 2 Relationship between the expression of AR and molecular typing characteristics

Variable	Patients	AR + (%)	AR-(%)	χ2	p	
ER					5.357e-15	
 ER + 	293	281(95.6%)	12(4.1%)	61.125		
 ER-	139	96(69.06%)	43(30.94%)			
PR					9.594e-11	
 PR + 	259	248(95.75%)	11(4.25%)	41.903		
 PR-	173	129(74.57%)	44(25.43%)			
Her-2					8.408e-05	
 Her-2 + 	135	131(97.04%)	4(2.96%)	18.767		
 Her-2-	290	239(82.41%)	51(17.59%)			
 Unknown	7	7(100%)	0			
Ki67					0.0458	
 ≤ 14	39	38(97.44%)	1(2.56%)	3.9888		
  > 14%	393	339(86.26%)	54(13.74%)			
Subtype					 < 2.2e-16	
 Luminal stype	206	194(94.17%)	12(5.83%0	103.44		
 HR-Her-2 + 	54	49(90.74%)	5(9.26%)			
 HR + Her-2 + 	83	83(100%)	0			
 TNBC	82	44(53.66%)	38(46.34%)			

Expression difference of AR in TNBC and non-TNBC tissues

Among the patients, 82 (18.98%) patients were TNBC with 44 AR-positive cases (53.66%), and 350 (95.14%) patients were non-TNBC with 333 AR-positive cases (95.14%). AR expressions were significantly different between the TNBC group and the non-TNBC group (p < 2.2e-16) (Table 3). Table 3 Difference analysis of AR expression in triple negative and non-triple negative breast cancer tissues

Variable	Patients	AR(%)		
TNBC	N	 + 	-	
non-TNBC	350	333(95.14%)	17(4.86%)	
TNBC	82	44(53.66%)	38(46.34%)	
χ2		102.9		
P		 < 2.2e-16		

Multivariate analysis with significant factors

Multivariate logistic regression confirmed ER, PR and Her-2 as independent predictors for AR expression (p < 0.05). In addition, AR expression was significantly related to tumor recurrence (p < 0.05) (Table 4). Table 4 Logistic regression analysis of AR expression and clinico-pathological factors

Factor	B	SE	Wald	OR	95%CI	p	
	0.55254	0.29035	3.62141				
Age	1	2	5	1.737662	[0.9849–3.0899]	0.05704	
menopaus	0.26548	0.28896	0.84407			0.35823	
e	1	3	8	1.304059	[0.7389–2.3053]	3	
T	-0.23631

0.20025

	4

0.32777

	3

0.37327

	0.789533	[0.4192–1.4587]	9

0.54122

	
N	9	5	8	1.221719	[0.6485–2.3625]	3	
M	-1.24479	1.23336 3	1.01862 3	0.288	[0.0271–6.2588]	0.31284 6	
Stage	-0.09692	0.38399 1	0.06371	0.907626	[0.4192–1.9121]	0.80072 5	
ER	2.3503	0.34722 4	45.8170 4	10.48872	[5.4701–21.5687]	1.3E-11	
PR	2.03991 1	0.3541	33.1871 1	7.689922	[2.9743–16.1293]	8.37E09	
Her-2	1.94426 5	0.53049 6	13.4322 1	6.988494	[2.7786–23.4905]	0.00024 7	
Ki67	-1.80057	1.02360 5	3.09425	0.165205	[0.0092–0.7873]	0.07856 9	
Stype	19.4194 7	1180.40 6	0.00027 1	2.71E + 0

8

	[2.91E-13-

2.9E + 182]

	0.98687 4	
pCR	0.43610 2	0.65871 7	0.43830 8	1.546667	[0.3827–5,3731]	0.50794	
Grade	-12.6021	727.698 9	0.0003	3.36E-06	[NA-3.92E + 30]	0.98618 3	
Recurrence	-2.2094	0.62431	12.5241 1	0.109767	[0.0306–0.3773]	0.00040 2	

Discussion

Breast cancer is hormone-dependent and routinely examined with ER/PR and AR, ER belong to the nuclear receptor superfamily [15–17]. Although AR has the same structure as ER/PR and is more extensively expressed AR is far less understood than ER and PR. We investigated the AR expression in breast cancer patients and correlated it with clinical-pathological characteristics.

We observed AR expression in about 87.3% (n = 377/432) of the cases in our cohort. This large proportion of AR expression is consistent with the literature. Research AR plays an important role in the pathogenesis of breast cancer, and is expressed in more than 70% breast cancer patients [18]. Other studies show the presence of AR in ER-positive breast cancer is correlated with tumor size, and histopathological grading [19, 20]. However, our investigation found AR expression was significantly associated with independent risk factors (e.g., ER, PR, Her-2 and Ki-67), but not with clinical-pathological characteristics (e.g., age, menopausal status, tumor size, lymph node, distant metastasis tumor stage) in breast cancer patients. This result may suggest AR is correlated with the histological subtype, and can be adopted as a potential biomarker.

The AR positive rate in ER-positive breast cancers is 66.9%, which is consistent with the reported rate of 60%-90% [17, 20, 21]. However, some studies indicate AR may act as a tumor suppressor in this sub-type [22, 23]. Meanwhile, AR expression is correlated with ER. One of the most likely mechanisms is that AR can competitively combine estrogen responsive elements to inhibit the transcriptionally active components of ER [22]. In addition, AR can directly bind to p300, a coactivator for competitive binding with ER, and then inhibits the function and downstream signaling pathways of ER [22], thus suppressing tumor growth in luminal breast cancer. Indeed, AR is also regarded as a good prognostic factor. For instance, the presence of AR in ER-positive breast cancer patients shows a better prognostic outcome in terms of DFS and OS [24, 25]. In HR + /Her2-T2N0 breast cancer, AR-positive patients have better DFS and lower risk of recurrence. In addition, AR negativity predicts a worse curative effect for adjuvant chemotherapy and endocrine therapy [13]. We did not discover significant relations between AR expression and time-to-event outcomes, which is because we did not follow up our patients for a long time and we will follow up full life.

AR expression accounts for 60% in Her-2-positive breast cancer patients, but the AR expression rate is low in this sub-type in our work, which may be related to the small sample size. Moreover, AR expression in Her-2-positive breast cancer patients predicts a worse prognosis, which may be involved in mediating Wnt/β catenin and Her-2 signaling pathways [26]. To the delight, we are conducting clinical trials on enzalutamide combined with trastuzumab for Her-2+/AR+ breast cancer patients, and hope to achieve good results.

As we know, TNBC have high heterogeneity and lacks target therapy, such as Her-2 and HR that predict poor prognosis and early metastasis. However, more than 50% of TNBC cases express AR, and more evidences suggest AR to be a solid target. Thike et Al. (2014) found AR-positive TNBC was related to better DFS [27]. Howeverother studies present opposite results. For instance, a clinical study with 559 TNBC cases shows AR negativity is correlated with a better prognostic outcome in terms of OS. For TNBC patients without lymph node metastasis, AR-positive patients also have a higher risk of death and recurrence [20, 24, 28]. Therefore, we are required to confirm the clinical role of AR. A. Di Leone disclosed that AR overexpression in TNBC showed a lower Ki67 rate and was related to a lower rate of pCR in neoadjuvant chemotherapy [29]. Currently, researchers pay more attention to TNBC to ensure long survival. In this aspect, AR-target therapy gives the choice for TNBC, which also need more clinical trials.

In summary, in-depth research on targeted therapy and combination therapy for breast cancer is demanded. Routine assessment of AR may help better personalize treatment for breast cancer, and can be used as a potential therapeutic target and novel biomarker in breast cancer. Furthermore, extensive research containing a large substantiation in patients, and more controlled prospective clinical trials are needed to validate the results.

Acknowledgements

None.

Authors’ contributions

HDZ and SLZ designed the study and wrote the manuscript. DDW and LHJ primarily wrote the manuscript and prepared the tables. JZ and XC made substantial contributions to the acquisition and analysis of data. JZ and HLZ made contributions to the analysis and interpretation of data and revised the manuscript. All authors have read and approved the final manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (No. 82102780, 82303449), High-level Innovative and Entrepreneurial Talent Introduction Plan of Jiangsu Province (303073540ER21), Scientific Research Project of Jiangsu Provincial Health Commission (H2023088), and National Natural Science Foundation Youth Fund Cultivation Program of the First Affiliated Hospital of Nanjing Medical University (PY2022030), and Jiangsu Province Hospital (the First Affiliated Hospital with Nanjing Medical University) Clinical Capacity Enhancement Project (JSPH-MC-2022–26).

Availability of data and materials

The datasets used and/or analyzed in the present study are available from the corresponding author on reasonable request.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

In this research were approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Ethics code 2022-SR-473), which deemed that written informed consent was not necessary due to the retrospectiveness of the research and the concealment of patient information.

Competing interests

The authors declare no competing interests.

He-da Zhang is the first corresponding author.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dan-dan Wang, Lin-hong Jiang and Jian Zhang contributed equally to this work.
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References

1. Siegel RL Miller KD Fuchs HE Jemal A Cancer statistics, 2022 CA Cancer J Clin 2022 72 7 33 10.3322/caac.21708 35020204
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33. 10.3322/caac.21708.35020204 10.3322/caac.21708
2. Anestis A, Zoi I, Papavassiliou AG and Karamouzis MV (2020) Androgen Receptor in Breast Cancer-Clinical and Preclinical Research Insights. Molecules 25. 10.3390/molecules25020358
3. Vasiliou SK Diamandis EP Androgen receptor: A promising therapeutic target in breast cancer Crit Rev Clin Lab Sci 2019 56 200 223 10.1080/10408363.2019.1575643 30821186
Vasiliou SK, Diamandis EP. Androgen receptor: A promising therapeutic target in breast cancer. Crit Rev Clin Lab Sci. 2019;56:200–23. 10.1080/10408363.2019.1575643.30821186 10.1080/10408363.2019.1575643
4. Elebro K Borgquist S Simonsson M Markkula A Jirström K Ingvar C Rose C Jernström H Combined Androgen and Estrogen Receptor Status in Breast Cancer: Treatment Prediction and Prognosis in a Population-Based Prospective Cohort Clin Cancer Res 2015 21 3640 3650 10.1158/1078-0432.Ccr-14-2564 25904752
Elebro K, Borgquist S, Simonsson M, Markkula A, Jirström K, Ingvar C, Rose C, Jernström H. Combined Androgen and Estrogen Receptor Status in Breast Cancer: Treatment Prediction and Prognosis in a Population-Based Prospective Cohort. Clin Cancer Res. 2015;21:3640–50. 10.1158/1078-0432.Ccr-14-2564.25904752 10.1158/1078-0432.Ccr-14-2564
5. Lehmann BD Bauer JA Chen X Sanders ME Chakravarthy AB Shyr Y Pietenpol JA Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies J Clin Invest 2011 121 2750 2767 10.1172/jci45014 21633166
Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–67. 10.1172/jci45014.21633166 10.1172/jci45014
6. He L Du Z Xiong X Ma H Zhu Z Gao H Cao J Li T Li H Yang K Chen G Richer JK Gu H Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer Sci Rep 2017 7 14584 10.1038/s41598-017-14607-2 29109513
He L, Du Z, Xiong X, Ma H, Zhu Z, Gao H, Cao J, Li T, Li H, Yang K, Chen G, Richer JK, Gu H. Targeting Androgen Receptor in Treating HER2 Positive Breast Cancer. Sci Rep. 2017;7:14584. 10.1038/s41598-017-14607-2.29109513 10.1038/s41598-017-14607-2
7. 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 13 154 166 10.1593/neo.101324 21403841
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. 10.1593/neo.101324.21403841 10.1593/neo.101324
8. De Amicis F Thirugnansampanthan J Cui Y Selever J Beyer A Parra I Weigel NL Herynk MH Tsimelzon A Lewis MT Chamness GC Hilsenbeck SG Andò S Fuqua SA Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells Breast Cancer Res Treat 2010 121 1 11 10.1007/s10549-009-0436-8 19533338
De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, Weigel NL, Herynk MH, Tsimelzon A, Lewis MT, Chamness GC, Hilsenbeck SG, Andò S, Fuqua SA. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat. 2010;121:1–11. 10.1007/s10549-009-0436-8.19533338 10.1007/s10549-009-0436-8
9. Dorgan JF Stanczyk FZ Egleston BL Kahle LL Shaw CM Spittle CS Godwin AK Brinton LA Prospective case-control study of serum mullerian inhibiting substance and breast cancer risk J Natl Cancer Inst 2009 101 1501 1509 10.1093/jnci/djp331 19820206
Dorgan JF, Stanczyk FZ, Egleston BL, Kahle LL, Shaw CM, Spittle CS, Godwin AK, Brinton LA. Prospective case-control study of serum mullerian inhibiting substance and breast cancer risk. J Natl Cancer Inst. 2009;101:1501–9. 10.1093/jnci/djp331.19820206 10.1093/jnci/djp331
10. Kaaks R Berrino F Key T Rinaldi S Dossus L Biessy C Secreto G Amiano P Bingham S Boeing H Bueno de Mesquita HB Chang-Claude J Clavel-Chapelon F Fournier A van Gils CH Gonzalez CA Gurrea AB Critselis E Khaw KT Krogh V Lahmann PH Nagel G Olsen A Onland-Moret NC Overvad K Palli D Panico S Peeters P Quirós JR Roddam A Thiebaut A Tjønneland A Chirlaque MD Trichopoulou A Trichopoulos D Tumino R Vineis P Norat T Ferrari P Slimani N Riboli E Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) J Natl Cancer Inst 2005 97 755 765 10.1093/jnci/dji132 15900045
Kaaks R, Berrino F, Key T, Rinaldi S, Dossus L, Biessy C, Secreto G, Amiano P, Bingham S, Boeing H, Bueno de Mesquita HB, Chang-Claude J, Clavel-Chapelon F, Fournier A, van Gils CH, Gonzalez CA, Gurrea AB, Critselis E, Khaw KT, Krogh V, Lahmann PH, Nagel G, Olsen A, Onland-Moret NC, Overvad K, Palli D, Panico S, Peeters P, Quirós JR, Roddam A, Thiebaut A, Tjønneland A, Chirlaque MD, Trichopoulou A, Trichopoulos D, Tumino R, Vineis P, Norat T, Ferrari P, Slimani N, Riboli E. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2005;97:755–65. 10.1093/jnci/dji132.15900045 10.1093/jnci/dji132
11. Fourkala EO Zaikin A Burnell M Gentry-Maharaj A Ford J Gunu R Soromani C Hasenbrink G Jacobs I Dawnay A Widschwendter M Lichtenberg-Fraté H Menon U Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women Endocr Relat Cancer 2012 19 137 147 10.1530/erc-11-0310 22199143
Fourkala EO, Zaikin A, Burnell M, Gentry-Maharaj A, Ford J, Gunu R, Soromani C, Hasenbrink G, Jacobs I, Dawnay A, Widschwendter M, Lichtenberg-Fraté H, Menon U. Association of serum sex steroid receptor bioactivity and sex steroid hormones with breast cancer risk in postmenopausal women. Endocr Relat Cancer. 2012;19:137–47. 10.1530/erc-11-0310.22199143 10.1530/erc-11-0310
12. Feng J Li L Zhang N Liu J Zhang L Gao H Wang G Li Y Zhang Y Li X Liu D Lu J Huang B Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms Oncogene 2017 36 2775 2790 10.1038/onc.2016.432 27893717
Feng J, Li L, Zhang N, Liu J, Zhang L, Gao H, Wang G, Li Y, Zhang Y, Li X, Liu D, Lu J, Huang B. Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms. Oncogene. 2017;36:2775–90. 10.1038/onc.2016.432.27893717 10.1038/onc.2016.432
13. Zhong W Yi J Wu H Zou X Feng J Huang X Li S Wang X Androgen receptor expression and its prognostic value in T1N0 luminal/HER2- breast cancer Future Oncol 2022 18 1745 1756 10.2217/fon-2021-1300 35227076
Zhong W, Yi J, Wu H, Zou X, Feng J, Huang X, Li S, Wang X. Androgen receptor expression and its prognostic value in T1N0 luminal/HER2- breast cancer. Future Oncol. 2022;18:1745–56. 10.2217/fon-2021-1300.35227076 10.2217/fon-2021-1300
14. Goldhirsch A Wood WC Coates AS Gelber RD Thürlimann B Senn HJ Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 Ann Oncol 2011 22 1736 1747 10.1093/annonc/mdr304 21709140
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ. Strategies for subtypes–dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22:1736–47. 10.1093/annonc/mdr304.21709140 10.1093/annonc/mdr304
15. Wang D Tang M Zhang P Yang K Huang L Wu M Shen Q Yue J Wang W Gong Y Warner M Dai L He H Yang Z Gustafsson JA Zhou S Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer Proc Natl Acad Sci U S A 2024 121 e2306814121 10.1073/pnas.2306814121 38513102
Wang D, Tang M, Zhang P, Yang K, Huang L, Wu M, Shen Q, Yue J, Wang W, Gong Y, Warner M, Dai L, He H, Yang Z, Gustafsson JA, Zhou S. Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer. Proc Natl Acad Sci U S A. 2024;121:e2306814121. 10.1073/pnas.2306814121.38513102 10.1073/pnas.2306814121
16. Sawada T Kanemoto Y Kurokawa T Kato S The epigenetic function of androgen receptor in prostate cancer progression Front Cell Dev Biol 2023 11 1083486 10.3389/fcell.2023.1083486 37025180
Sawada T, Kanemoto Y, Kurokawa T, Kato S. The epigenetic function of androgen receptor in prostate cancer progression. Front Cell Dev Biol. 2023;11:1083486. 10.3389/fcell.2023.1083486.37025180 10.3389/fcell.2023.1083486
17. Narayanan R and Dalton JT (2016) Androgen Receptor: A Complex Therapeutic Target for Breast Cancer. Cancers (Basel) 8. 10.3390/cancers8120108
18. Collins LC Cole KS Marotti JD 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 24 924 931 10.1038/modpathol.2011.54 21552212
Collins LC, Cole KS, Marotti JD, 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. 10.1038/modpathol.2011.54.21552212 10.1038/modpathol.2011.54
19. Witzel I Graeser M Karn T Schmidt M Wirtz R Schütze D Rausch A Jänicke F Milde-Langosch K Müller V Androgen receptor expression is a predictive marker in chemotherapy-treated patients with endocrine receptor-positive primary breast cancers J Cancer Res Clin Oncol 2013 139 809 816 10.1007/s00432-013-1382-8 23392859
Witzel I, Graeser M, Karn T, Schmidt M, Wirtz R, Schütze D, Rausch A, Jänicke F, Milde-Langosch K, Müller V. Androgen receptor expression is a predictive marker in chemotherapy-treated patients with endocrine receptor-positive primary breast cancers. J Cancer Res Clin Oncol. 2013;139:809–16. 10.1007/s00432-013-1382-8.23392859 10.1007/s00432-013-1382-8
20. You CP, Leung MH, Tsang WC, Khoo US and Tsoi H (2022) Androgen Receptor as an Emerging Feasible Biomarker for Breast Cancer. Biomolecules 12. 10.3390/biom12010072
21. Kono M Fujii T Lim B Karuturi MS Tripathy D Ueno NT Androgen Receptor Function and Androgen Receptor-Targeted Therapies in Breast Cancer: A Review JAMA Oncol 2017 3 1266 1273 10.1001/jamaoncol.2016.4975 28301631
Kono M, Fujii T, Lim B, Karuturi MS, Tripathy D, Ueno NT. Androgen Receptor Function and Androgen Receptor-Targeted Therapies in Breast Cancer: A Review. JAMA Oncol. 2017;3:1266–73. 10.1001/jamaoncol.2016.4975.28301631 10.1001/jamaoncol.2016.4975
22. Hickey TE Selth LA Chia KM Laven-Law G Milioli HH Roden D Jindal S Hui M Finlay-Schultz J Ebrahimie E Birrell SN Stelloo S Iggo R Alexandrou S Caldon CE Abdel-Fatah TM Ellis IO Zwart W Palmieri C Sartorius CA Swarbrick A Lim E Carroll JS Tilley WD The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer Nat Med 2021 27 310 320 10.1038/s41591-020-01168-7 33462444
Hickey TE, Selth LA, Chia KM, Laven-Law G, Milioli HH, Roden D, Jindal S, Hui M, Finlay-Schultz J, Ebrahimie E, Birrell SN, Stelloo S, Iggo R, Alexandrou S, Caldon CE, Abdel-Fatah TM, Ellis IO, Zwart W, Palmieri C, Sartorius CA, Swarbrick A, Lim E, Carroll JS, Tilley WD. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat Med. 2021;27:310–20. 10.1038/s41591-020-01168-7.33462444 10.1038/s41591-020-01168-7
23. You CP, Tsoi H, Man EPS, Leung MH and Khoo US (2022) Modulating the Activity of Androgen Receptor for Treating Breast Cancer. Int J Mol Sci 23. 10.3390/ijms232315342
24. Hu R Dawood S Holmes MD Collins LC Schnitt SJ Cole K Marotti JD Hankinson SE Colditz GA Tamimi RM Androgen receptor expression and breast cancer survival in postmenopausal women Clin Cancer Res 2011 17 1867 1874 10.1158/1078-0432.Ccr-10-2021 21325075
Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, Marotti JD, Hankinson SE, Colditz GA, Tamimi RM. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17:1867–74. 10.1158/1078-0432.Ccr-10-2021.21325075 10.1158/1078-0432.Ccr-10-2021
25. Kensler KH Poole EM Heng YJ Collins LC Glass B Beck AH Hazra A Rosner BA Eliassen AH Hankinson SE Winer EP Brown M Tamimi RM Androgen Receptor Expression and Breast Cancer Survival: Results From the Nurses' Health Studies J Natl Cancer Inst 2019 111 700 708 10.1093/jnci/djy173 30445651
Kensler KH, Poole EM, Heng YJ, Collins LC, Glass B, Beck AH, Hazra A, Rosner BA, Eliassen AH, Hankinson SE, Winer EP, Brown M, Tamimi RM. Androgen Receptor Expression and Breast Cancer Survival: Results From the Nurses’ Health Studies. J Natl Cancer Inst. 2019;111:700–8. 10.1093/jnci/djy173.30445651 10.1093/jnci/djy173
26. Kolyvas EA Caldas C Kelly K Ahmad SS Androgen receptor function and targeted therapeutics across breast cancer subtypes Breast Cancer Res 2022 24 79 10.1186/s13058-022-01574-4 36376977
Kolyvas EA, Caldas C, Kelly K, Ahmad SS. Androgen receptor function and targeted therapeutics across breast cancer subtypes. Breast Cancer Res. 2022;24:79. 10.1186/s13058-022-01574-4.36376977 10.1186/s13058-022-01574-4
27. Thike AA Yong-Zheng Chong L Cheok PY Li HH Wai-Cheong Yip G Huat Bay B Tse GM Iqbal J Tan PH Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer Mod Pathol 2014 27 352 360 10.1038/modpathol.2013.145 23929266
Thike AA, Yong-Zheng Chong L, Cheok PY, Li HH, Wai-Cheong Yip G, Huat Bay B, Tse GM, Iqbal J, Tan PH. Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer. Mod Pathol. 2014;27:352–60. 10.1038/modpathol.2013.145.23929266 10.1038/modpathol.2013.145
28. Choi JE Kang SH Lee SJ Bae YK Androgen receptor expression predicts decreased survival in early stage triple-negative breast cancer Ann Surg Oncol 2015 22 82 89 10.1245/s10434-014-3984-z 25145503
Choi JE, Kang SH, Lee SJ, Bae YK. Androgen receptor expression predicts decreased survival in early stage triple-negative breast cancer. Ann Surg Oncol. 2015;22:82–9. 10.1245/s10434-014-3984-z.25145503 10.1245/s10434-014-3984-z
29. Di Leone A Fragomeni SM Scardina L Ionta L Mulè A Magno S Terribile D Masetti R Franceschini G Androgen receptor expression and outcome of neoadjuvant chemotherapy in triple-negative breast cancer Eur Rev Med Pharmacol Sci 2021 25 1910 1915 10.26355/eurrev_202102_25087 33660830
Di Leone A, Fragomeni SM, Scardina L, Ionta L, Mulè A, Magno S, Terribile D, Masetti R, Franceschini G. Androgen receptor expression and outcome of neoadjuvant chemotherapy in triple-negative breast cancer. Eur Rev Med Pharmacol Sci. 2021;25:1910–5. 10.26355/eurrev_202102_25087.33660830 10.26355/eurrev_202102_25087
