scholarly journals Minireview: The Androgen Receptor in Breast Tissues: Growth Inhibitor, Tumor Suppressor, Oncogene?

2012 ◽  
Vol 26 (8) ◽  
pp. 1252-1267 ◽  
Author(s):  
T. E. Hickey ◽  
J. L. L. Robinson ◽  
J. S. Carroll ◽  
W. D. Tilley
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Growth Inhibitor ◽  
Estrogen Receptor Α ◽  
Normal Breast ◽  
Inhibitory Influence ◽  
Breast Cancers ◽  
Growth Inhibitory ◽  
Cancer Phenotypes

Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer.

scholarly journals Androgen Receptor as an Emerging Feasible Biomarker for Breast Cancer

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 72
Author(s):  
Chan-Ping You ◽  
Man-Hong Leung ◽  
Wai-Chung Tsang ◽  
Ui-Soon Khoo ◽  
Ho Tsoi
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Growth Factor Receptor ◽  
Estrogen Receptor Α ◽  
Nuclear Hormone Receptor ◽  
Tumor Promoter ◽  
Breast Cancers ◽  
Scoring Method ◽  
Poor Prognostic Factor ◽  
Prognosis And Prediction

Biomarkers can be used for diagnosis, prognosis, and prediction in targeted therapy. The estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) are standard biomarkers used in breast cancer for guiding disease treatment. The androgen receptor (AR), a nuclear hormone receptor, contributes to the development and progression of prostate tumors and other cancers. With increasing evidence to support that AR plays an essential role in breast cancer, AR has been considered a useful biomarker in breast cancer, depending on the context of breast cancer sub-types. The existing survival analyses suggest that AR acts as a tumor suppressor in ER + ve breast cancers, serving as a favorable prognostic marker. However, AR functions as a tumor promoter in ER-ve breast cancers, including HER2 + ve and triple-negative (TNBC) breast cancers, serving as a poor prognostic factor. AR has also been shown to be predictive of the potential of response to adjuvant hormonal therapy in ER + ve breast cancers and to neoadjuvant chemotherapy in TNBC. However, conflicting results do exist due to intrinsic molecular differences between tumors and the scoring method for AR positivity. Applying AR expression status to guide treatment in different breast cancer sub-types has been suggested. In the future, AR will be a feasible biomarker for breast cancer. Clinical trials using AR antagonists in breast cancer are active. Targeting AR alone or other therapeutic agents provides alternatives to existing therapy for breast cancer. Therefore, AR expression will be necessary if AR-targeted treatment is to be used.

scholarly journals Pushing estrogen receptor around in breast cancer

2016 ◽  
Vol 23 (12) ◽  
pp. T227-T241 ◽  
Author(s):  
Elgene Lim ◽  
Gerard Tarulli ◽  
Neil Portman ◽  
Theresa E Hickey ◽  
Wayne D Tilley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Clinical Problem ◽  
Estrogen Receptor Α ◽  
Normal Breast ◽  
Favourable Outcome ◽  
Breast Cancers ◽  
Er Positive ◽  
Tumorigenic Activity ◽  
Positive Breast Cancer

The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments. Emerging data have shown that other SSRs may regulate the sites at which ER binds to DNA in ways that can powerfully suppress the oncogenic activity of ER in breast cancer. This includes the progesterone receptor (PR) that was recently shown to reprogram the ER DNA binding landscape towards genes associated with a favourable outcome. Another attractive candidate is the androgen receptor (AR), which is expressed in the majority of breast cancers and inhibits growth of the normal breast and ER-positive tumours when activated by ligand. These findings have led to the initiation of breast cancer clinical trials evaluating therapies that selectively harness the ability of SSRs to ‘push’ ER towards anti-tumorigenic activity. Our review will focus on the established and emerging clinical evidence for activating PR or AR in ER-positive breast cancer to inhibit the tumour growth-promoting functions of ER.

scholarly journals The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1160
Author(s):  
Giusi La Camera ◽  
Luca Gelsomino ◽  
Amanda Caruso ◽  
Salvatore Panza ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Disease Recurrence ◽  
Estrogen Receptor Α ◽  
Research Area ◽  
Tumor Evolution

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression.

scholarly journals Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

2014 ◽  
Vol 8 ◽  
pp. BCBCR.S9453 ◽  
Author(s):  
Adam M. Brufsky
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Intrinsic Resistance ◽  
Her2 Positive

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.

scholarly journals Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4972
Author(s):  
Sanjeev Kumar ◽  
Allegra Freelander ◽  
Elgene Lim
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Patient Outcomes ◽  
Estrogen Receptor Α ◽  
Receptor Activity ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Major Breast

The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.

Calcineurin regulates the stability and activity of estrogen receptor α

2021 ◽  
Vol 118 (44) ◽  
pp. e2114258118
Author(s):  
Takahiro Masaki ◽  
Makoto Habara ◽  
Yuki Sato ◽  
Takahiro Goshima ◽  
Keisuke Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
The Stability ◽  
Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

scholarly journals Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2482
Author(s):  
Samson Mathews Samuel ◽  
Elizabeth Varghese ◽  
Lenka Koklesová ◽  
Alena Líšková ◽  
Peter Kubatka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Acquired Resistance ◽  
Breast Cancers ◽  
Intrinsic Resistance ◽  
Mesenchymal Transition ◽  
Cancer Breast

Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.

scholarly journals Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

2008 ◽  
Vol 11 (2) ◽  
Author(s):  
Alison J. Butt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Xenograft Model ◽  
Estrogen Receptor Α ◽  
Tumor Xenograft ◽  
Breast Cancers ◽  
Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

scholarly journals Identification of Long Noncoding RNAs as Predictors of Survival in Triple-Negative Breast Cancer Based on Network Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Xiao-Xiao Li ◽  
Li-Juan Wang ◽  
Jie Hou ◽  
Hong-Yang Liu ◽  
Rui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Breast Cancers ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes

Breast cancer is the most common cancer observed in adult females, worldwide. Due to the heterogeneity and varied molecular subtypes of breast cancer, the molecular mechanisms underlying carcinogenesis in different subtypes of breast cancer are distinct. Recently, long noncoding RNAs (lncRNAs) have been shown to be oncogenic or play important roles in cancer suppression and are used as biomarkers for diagnosis and therapy. In this study, we identified 134 lncRNAs and 6,414 coding genes were differentially expressed in triple-negative (TN), human epidermal growth factor receptor 2- (HER2-) positive, luminal A-positive, and luminal B-positive breast cancer. Of these, 37 lncRNAs were found to be dysregulated in all four subtypes of breast cancers. Subtypes of breast cancer special modules and lncRNA-mRNA interaction networks were constructed through weighted gene coexpression network analysis (WGCNA). Survival analysis of another public datasets was used to verify the identified lncRNAs exhibiting potential indicative roles in TN prognosis. Results from heat map analysis of the identified lncRNAs revealed that five blocks were significantly displayed. High expressions of lncRNAs, including LINC00911, CSMD2-AS1, LINC01192, SNHG19, DSCAM-AS1, PCAT4, ACVR28-AS1, and CNTFR-AS1, and low expressions of THAP9-AS1, MALAT1, TUG1, CAHM, FAM2011, NNT-AS1, COX10-AS1, and RPARP-AS1 were associated with low survival possibility in TN breast cancers. This study provides novel lncRNAs as potential biomarkers for the therapeutic and prognostic classification of different breast cancer subtypes.

Breast cancers with stem cell-like features delineate endocrine responsiveness

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10517-10517
Author(s):  
A. Rody ◽  
T. Karn ◽  
C. Solbach ◽  
R. Gaetje ◽  
R. Diallo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Lymph Node ◽  
Survival Rates ◽  
Disease Recurrence ◽  
Normal Breast ◽  
Endocrine Treatment ◽  
Breast Cancers ◽  
Er Positive ◽  
Er Status

10517 Background: Endocrine responsiveness is one of the most important characteristics of breast cancer. The negative association between expression of the estrogen receptor (ER) and proliferation detected in normal breast is frequently lost in breast cancers leading to receptor independent growth and poor patients’ prognosis. Methods: Microarray analysis of 171 breast cancer samples allowed the discrimination of a KIT+ tumor group by using a set of genes coregulated with the “stem cell factor” receptor KIT. Validation was performed on three independent datasets encompassing 637 samples. Furthermore the response to endocrine treatment only was analyzed in a dataset of 700 patients. Results: KIT+ tumors are transcriptionally related to proposed mammary stem cells. Two types of KIT+ tumors were identified which are characterized by their positive and negative ER status, respectively. The inverse link of ER expression and proliferation is perfectly conserved within the KIT+ tumor groups, while it is uncoupled among half of the KIT-Low ER positive tumors. Those “uncoupled” ER positive tumors with altered ER response are characterized by a prognosis inferior to the ER negative cancers despite an apparent positive ER status (hazard ratio for disease recurrence, 2.07; 95% CI 1.53–2.81; P<0.001). Moreover, the 5 and 10 year survival rates of lymph node negative “uncoupled” tumors are even worse than those of lymph node positive “normal” ER positive cancers. While all ER positive patients seem to profit from endocrine treatment the relative benefit was reduced in uncoupled tumors (21.2 % vs. 31.7 %). Conclusions: The classification of breast cancers according to this biologically based model identified clinical relevant tumor groups whose further characterization will have important implications. Moreover, since the ability to recognize malfunctions in ER pathways largely depends on an appropriate reference system, the KIT+ tumors could allow a dissection of estrogen responsiveness giving crucial insights for prediction of response to endocrine therapy. No significant financial relationships to disclose.

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