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

2017 ◽  
Vol 43 (5) ◽  
pp. 2047-2061 ◽  
Author(s):  
Yan Shen ◽  
Fang Yang ◽  
Wenwen Zhang ◽  
Wei Song ◽  
Yuxiu Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
G Protein ◽  
Triple Negative Breast Cancer ◽  
Cellular Proliferation ◽  
Triple Negative ◽  
Predictive Marker ◽  
Tissue Microarrays ◽  
G Protein Coupled

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.

scholarly journals Regulation of ERRα Gene Expression by Estrogen Receptor Agonists and Antagonists in SKBR3 Breast Cancer Cells: Differential Molecular Mechanisms Mediated by G Protein-Coupled Receptor GPR30/GPER-1

2010 ◽  
Vol 24 (5) ◽  
pp. 969-980 ◽  
Author(s):  
Yin Li ◽  
Lutz Birnbaumer ◽  
Christina T. Teng
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
G Protein ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
G Protein Coupled Receptor ◽  
Ici 182,780 ◽  
G Protein Coupled

Abstract In selected tissues and cell lines, 17β-estradiol (E2) regulates the expression of estrogen-related receptor α (ERRα), a member of the orphan nuclear receptor family. This effect is thought to be mediated by the estrogen receptor α (ERα). However in the ERα- and ERβ-negative SKBR3 breast cancer cell line, physiological levels of E2 also stimulate ERRα expression. Here, we explored the molecular mechanism that mediates estrogen action in ER-negative breast cancer cells. We observed that E2, the ERα agonist, as well as the ERα antagonists ICI 182,780 and tamoxifen (TAM), a selective ER modulator, stimulate the transcriptional activity of the ERRα gene and increase the production of ERRα protein in SKBR3 cells. Moreover, the ERRα downstream target genes expression and cellular proliferation are also increased. We show further that the G protein-coupled receptor GPR30/GPER-1 (GPER-1) mediates these effects. The GPER-1 specific ligand G-1 mimics the actions of E2, ICI 182,780, and TAM on ERRα expression, and changing the levels of GPER-1 mRNA by overexpression or small interfering RNA knockdown affected the expression of ERRα accordingly. Utilizing inhibitors, we delineate a different downstream pathway for ER agonist and ER antagonist-triggered signaling through GPER-1. We also find differential histone acetylation and transcription factor recruitment at distinct nucleosomes of the ERRα promoter, depending on whether the cells are activated with E2 or with ER antagonists. These findings provide insight into the molecular mechanisms of GPER-1/ERRα-mediated signaling and may be relevant to what happens in breast cancer cells escaping inhibitory control by TAM.

scholarly journals The role of calcium and nitrite in triple negative breast cancer

2017 ◽  
Vol 1 (4) ◽  
Author(s):  
Dalal Alkuraythi
Keyword(s):  
Breast Cancer ◽  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Channel Blockers ◽  
Oxide Synthase ◽  
Estrogen Receptor Negative

In 2017, approximately 252,000 of American women were diagnosed with breast cancer of which ~25% of these cases were classified as estrogen receptor-negative (ER-). A substantial subset of these breast tumors do not express estrogen or progesterone receptors nor do they overexpress HER2 and have been therefore designated as triple negative breast cancers (TNBC). TNBC has been shown to be more aggressive and have poor prognosis. Androgen receptor (AR) is expressed in ~70% of ER- breast cancer. Even though, the ER role in breast cancer is well known and recognized, little is known about the clinical importance of androgens and AR in breast carcinogenesis. Ligand bound AR translocates to the nucleus, and then a cascade of events occurs culminating with transcription of target genes. Aim: Hypothesizing that activation of androgen receptor (AR) by calcium or nitrite results in increased proliferation in AR+ TNBC, hence creating an opportunity to be able to attack triple negative breast cancer cells via the androgen receptor and thereby be able to shrink the cancerous cells. Methods: Estrogen receptor negative, androgen receptor positive MDA-MB 453 breast cancer cells were treated with synthetic androgen (R1881); non-steroidal anti-androgens casodex, flutamide, or hydroxyl flutamide; calcium channel blockers mibefradil (T type) and methoxyverapamil (L type); or nitric oxide synthase inhibitor nitroarginine (LNNA) for 96h. Results: Cells treated with calcium showed a higher proliferation rate in comparison to control cells. In contrast cells treated with methoxyverapamil or mibefradil at higher concentrations, showed decreased cell growth. Conclusion: Data suggest that the overexpression of calcium channels and nitric oxide synthase, one or both of them, is a major contributor in activating androgen receptor leading to cell growth and survival of androgen receptor-positive breast cancer, and hence androgen activation in triple negative breast cancer. The data also suggest that FDA approved calcium channel blockers and NOS inhibitors maybe useful for the treatment of AR+ TNBC.  

scholarly journals G protein-coupled KISS1 receptor is overexpressed in triple negative breast cancer and promotes drug resistance

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Alexandra Blake ◽  
Magdalena Dragan ◽  
Rommel G. Tirona ◽  
Daniel B. Hardy ◽  
Muriel Brackstone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
G Protein ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
G Protein Coupled

Adipophilin expression as an independent marker for poor prognosis of patients with triple-negative breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12552-e12552
Author(s):  
Katsuhiro Yoshikawa ◽  
Mitsuaki Ishida ◽  
Hirotsugu Yanai ◽  
Koji Tsuta ◽  
Mitsugu Sekimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Marker ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Cellular Proliferation ◽  
Triple Negative ◽  
Expression Profiles ◽  
Tissue Microarrays ◽  
Glutamine Metabolism ◽  
Ki 67

e12552 Background: Adipophilin (ADP) is a lipid-regulating protein of the perilipin/adipophilin/tail interacting protein of 47 kDa (PAT) family that coats the surfaces of cytoplasmic lipid droplets. Lipids are essential for cellular proliferation in tumor cells, and ADP, which increases the efficiency of lipid use, may contribute to cancer growth. Some previous studies suggest that ADP expression can act as a prognostic marker for specific cancers. The aim of this study is to investigate the clinicopathological significance of ADP expression in patients with triple-negative breast cancer (TNBC). Methods: Using immunohistochemical staining and tissue microarrays, we analyzed the expression profiles of ADP, glutaminase, and glutamate dehydrogenase (key enzymes in glutamine metabolism) in 61 TNBC patients who underwent operation from January 2006–December 2018. Relapse-free survival (RFS) was compared based on ADP expression and the risk factors for RFS were analyzed. Results: Fourteen (23.0%) patients were ADP-positive. As compared to ADP-negative TNBC patients, ADP-positive TNBC patients correlated with poor RFS ( p = 0.032). Among the TNBC patients with high Ki-67 labeling index, those negative for ADP exhibited better RFS than those positive for ADP ( p = 0.049). Moreover, among the patients without adjuvant chemotherapy, those negative for ADP exhibited better RFS than those positive for ADP ( p = 0.080). ADP-positive patients correlated with a significantly higher recurrence based on multivariate analyses (hazard ratio, 4.89; 95% confidence interval, 1.04–23.0; p = 0.044). Moreover, ADP expression significantly correlated with the expression of glutaminase and glutaminate dehydrogenase ( p < 0.001 and p = 0.029, respectively). Conclusions: ADP expression is a novel marker for poor prognosis of patients with TNBC and might be superior to Ki-67 as a prognostic marker. ADP expression may be related to upregulation of glutamine metabolism in cancer cells of TNBC.

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