Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri, Elisabetta; Conteduca, Vincenza; Andreis, Daniele; Nanni, Oriana; Melegari, Elisabetta; Sarti, Samanta; Cecconetto, Lorenzo; Schirone, Alessio; Bravaccini, Sara; Serra, Patrizia; Fedeli, Anna; Maltoni, Roberta; Amadori, Dino; Giorgi, Ugo De; Rocca, Andrea

doi:10.1530/erc-16-0190

Cited by 82 publications

(73 citation statements)

References 81 publications

(87 reference statements)

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“…There is evidence suggesting that AR expression is about 60% among early breast cancers and is more frequently expressed in ER-positive than ER-negative breast cancers [41]. We speculate that ethnic differences might explain the variation in the percentage of the AR subtype between these different populations.…”

Section: Discussionmentioning

confidence: 84%

“…If we examine cell line-specific gene expression, although the AR gene in BT-549 (M) is upregulated compared to DU4475 (IM), MDA-MB-468 (BL1) and MDA-MB-231 (MSL), the AR gene transcript in MDA-MB-453 (LAR) is ninefold higher than in BT-549 (M), which suggests that this change in AR gene expression is specific to the LAR subtype. Recent discrepancies concerning the role of AR have been noted in various TNBC basic and clinical studies and both AR agonist and AR antagonist clinical trials have been designed for the treatment of TNBC and ER + breast cancers [41–43]. Thus, the therapeutic role of AR remains an open question.…”

Section: Discussionmentioning

confidence: 99%

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A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women

Tseng

Chiu

Liu

et al. 2017

Breast Cancer Res Treat

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Background“Precision medicine” is a concept that by utilizing modern molecular diagnostics, an effective therapy is accurately applied for each cancer patient to improve their survival rates. The treatment of triple-negative breast cancer (TNBC) remains a challenging issue. The aim of this study was to compare the molecular subtypes of triple-negative breast cancer (TNBC) between Taiwanese and Non-Asian women.MethodsGEO Datasets for non-Asian (12 groups, n = 1450) and Taiwanese (3 groups, n = 465) breast cancer, including 617 TNBC, were acquired, normalized and cluster analyzed. Then, using TNBC cell lines of different subtypes, namely, MDA-MB-468 (basal-like1, BL1), MDA-MB-231 (mesenchymal stem like, MSL), BT-549 (mesenchymal, M), MDA-MB-453 (luminal androgen receptor, LAR), and DU4475 (immunomodulatory, IM), real-time PCR in triplicate for 47 genes signatures were performed to validate the specificity of these subtypes.ResultsThe results showed that the percentage of TNBC subtypes in non-Asian women, namely, BL1, BL2, IM, M, MSL, and LAR was 13.56, 8.91, 16.80, 20.45, 8.30, and 11.13%, respectively. When data from Taiwanese were normalized and clustered, five TNBC subtypes, namely, BL (8.94%), IM (13.82%), M (22.76%), MSL (30.89%), and LAR (23.58%), were classified. Real-time PCR validated the specificity of these subtypes. Besides, the presence of interaction between IM- and MSL-subtypes suggests the involvement of tumor microenvironment in TNBC subtype classification.ConclusionOur data suggested that there exist different presentations between non-Asian and Taiwanese TNBC subtypes, which provides important information when selection of therapeutic targets or designs for clinical trials for TNBC patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4195-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women

Tseng

Chiu

Liu

et al. 2017

Breast Cancer Res Treat

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“…In a ligand-independent manner, AR is located in the cytoplasm and forms a complex with heat shock protein. While in a ligand-dependent manner AR binds with DHT, AR homodimer will then translocate to nuclear and interact with androgen responsive elements to regulate transcription of downstream genes [31]. Here, we reported that the activation of AR via DHT exhibits the proliferative effects on TNBC cell lines.…”

Section: Discussionmentioning

confidence: 93%

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

Shen

Yang

Zhang

et al. 2017

Cell Physiol Biochem

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Background/Aims: The targeted therapy for triple-negative breast cancer (TNBC) is still challenging due to poor understanding on its molecular etiology. The androgen receptor (AR) has recently emerged as a prognostic and treatment-predictive marker in breast cancer. However, the role of AR in TNBC remained elusive. Methods: Immunohistochemistry (IHC) was used to detect AR and G-protein coupled estrogen receptor (GPER) expression in tissue microarrays of 165 TNBC patients. Microarray analysis of mRNAs was performed to identify downstream regulators of AR. TNBC cells were cultured with dihydrotestosterone (DHT) alone or in combination with AR knockdown performed with AR shRNA. Cell viability and colony formation were assessed. Western blotting and qRT-PCR were used to examine protein and mRNA expression, respectively. The potential mechanism of AR-mediated GPER suppression was identified by Chromatin immunoprecipitation (ChIP) assay. AR and GPER expressions were also assessed in nude mouse xenografts by IHC. Results: IHC staining showed that the expression of AR was positively associated with tumor size, lymph node metastasis and high-grade tumor in TNBC patients. AR activation triggered by DHT suppressed GPER expression, to promote cell growth of TNBC. G-1, a GPER agonist, inhibited DHT-stimulated proliferation. Further experiments illustrated that AR suppressed GPER activation via binding directly to the promoter of GPER. Moreover, a negative correlation between AR and GPER was observed in MDA-MB-231 tumor cell xenografts and TNBC patient samples. Conclusions: The suppression of GPER via AR may be involved in the positive actions towards the TNBC progression, making it a promising therapeutic target for TNBC treatment.

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“…Recently, Pietri et al demonstrated an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios, including TNBC 28 . Considering that the main treatment of TNBC 29 is chemotherapy, in vitro studies show that AR activation can reduce chemotherapy efficacy in LAR subtype through the AR-mediated transcriptional regulation of pro-and anti-apoptotic genes, suggesting the usefulness of an AR block combined with chemotherapy in this setting 30 .…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor expression in triple negative breast cancer and its relationship to prognostic factors

Kneubil¹,

Godoy²,

Coelho³

et al. 2017

Rev. Bras. Mastol. (Impr.)

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Objetivo: O câncer de mama negativo triplo (triple negative breast cancer -TNBC) é um subtipo de tumores com biologia intrínseca agressiva, resultando em pior prognóstico. O receptor de andrógeno (androgen receptor -AR) é atualmente um dos biomarcadores mais estudados em TNBC, desempenhando papel na gênese e no desenvolvimento do câncer de mama. Métodos: Neste estudo transversal, revisamos retrospectivamente os registros médicos de todos os pacientes com TNBC que receberam atendimento de 2012 a 2014 em um único centro no sul do Brasil. O material histológico dos tumores de mama foi analisado por imuno-histoquímica para a expressão de AR e relacionado a idade, grau histológico, linfócitos infiltrantes de tumores (TILs) e Ki-67. Resultados: Dos 34 casos identificados de TNBC, 23 (67,6%) eram AR negativos e 11 (32,4%), AR positivos. A idade média foi de 51,9 anos (30-82 anos). Entre os casos positivos, AR foi fracamente expresso em 6 e fortemente expresso em 5 casos. A maioria dos pacientes (n=28, 82,0%) apresentou tumores pouco diferenciados. A expressão média de Ki-67 foi de 65,0% em AR-negativo e 43,6% em AR-positivo (p<0,05). Houve associação significativa entre a idade e a expressão de AR (p<0,005), associada à idade média de 70,8 anos no grupo Androgen receptor (AR) is currently one of the most studied biomarkers in TNBC, playing a role in the genesis and development of breast cancer. Methods: In this cross-sectional study, we retrospectively reviewed the medical records of all patients with TNBC who received care from 2012 to 2014 at a single health center in southern Brazil. Histological material from breast tumors was analyzed by immunohistochemistry for AR expression and related to age, histological grade, tumor-infiltrating lymphocytes (TILs), and Ki-67. Results: Of 34 TNBC cases identified, 23 (67.6%) were AR negative and 11 (32.4%) were AR positive. The average age of the patients was 51.9 years (range: 30-82 years). Among positive cases, AR was weakly expressed in 6 and strongly expressed in 5 cases. Most patients (n=28; 82.0%) had poorly differentiated tumors. Mean Ki-67 expression was 65.0% in AR-negative and 43.6% in AR-positive cases (p<0.05). There was a significant association between age and AR expression (p<0.005), which was associated with mean age 70.8 years in the strongly AR-positive group and 42.3 years in the weakly AR-positive group. The mean percentage of TILs was 38.6% in AR-positive and 39.1% in AR-negative cases (p=0.391). Conclusion: There was no significant association between AR expression and histological grade or TILs. AR positivity in TNBC was associated with older age and tumors with lower Ki-67 expression, indicating two subgroups with distinct phenotypes in patients with TNBC.

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Androgen receptor signaling pathways as a target for breast cancer treatment

Cited by 82 publications

References 81 publications

A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women

A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

Androgen receptor expression in triple negative breast cancer and its relationship to prognostic factors

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