scholarly journals GREB1 isoforms regulate proliferation independent of ERα co-regulator activities in breast cancer

2018 ◽  
Vol 25 (7) ◽  
pp. 735-746 ◽  
Author(s):  
Corinne N Haines ◽  
Kara M Braunreiter ◽  
Xiaokui Molly Mo ◽  
Craig J Burd
Keyword(s):  
Breast Cancer ◽  
Growth Regulation ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Gene Target ◽  
Elevated Expression ◽  
Malignant Breast ◽  
Exogenous Expression ◽  
Specific Regulation

Activation of the transcription factor estrogen receptor α (ERα) and the subsequent regulation of estrogen-responsive genes play a crucial role in the development and progression of the majority of breast cancers. One gene target of ERα, growth regulation by estrogen in breast cancer 1 (GREB1), is associated with proliferation and regulation of ERα activity in estrogen-responsive breast cancer cells. The GREB1 gene encodes three distinct isoforms: GREB1a, GREB1b and GREB1c, whose molecular functions are largely unknown. Here, we investigate the role of these isoforms in regulation of ERα activity and proliferation. Interaction between GREB1 and ERα was mapped to the amino terminus shared by all GREB1 variants. Analysis of isoform-specific regulation of ERα activity suggests none of the GREB1 isoforms possess potent co-regulator activity. Exogenous expression of GREB1a resulted in elevated expression of some ER-target genes, independent of ERα activity. Despite this slight specificity of GREB1a for gene regulation, exogenous expression of either GREB1a or GREB1b resulted in decreased proliferation in both ER-positive and ER-negative breast carcinoma cell lines, demonstrating an ER-independent function of GREB1. Interestingly, we show an increase in the expression of GREB1b and GREB1c mRNA in malignant breast tissue compared to normal patient samples, suggesting a selective preference for these isoforms during malignant transformation. Together, these data suggest GREB1a has an isoform-specific function as a transcriptional regulator while all isoforms share an ER-independent activity that regulates proliferation.

scholarly journals GREB1 regulates proliferation of estrogen receptor positive breast cancer through modulation of PI3K/Akt/mTOR signaling

2019 ◽  
Author(s):  
Corinne N. Haines ◽  
H.D. Klingensmith ◽  
Craig J. Burd
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Growth Regulation ◽  
Mtor Pathway ◽  
Estrogen Signaling ◽  
Molecular Function ◽  
Breast Cancers ◽  
Gene Target

AbstractOver 70% of breast cancers express the estrogen receptor (ER) and depend on ER activity for survival and proliferation. While hormone therapies that target receptor activity are initially effective, patients invariably develop resistance which is often associated with activation of the PI3K/Akt/mTOR pathway. While the mechanism by which estrogen regulates proliferation is not fully understood, one gene target of ER, growth regulation by estrogen in breast cancer 1 (GREB1), is required for hormone-dependent proliferation. However, the molecular function by which GREB1 regulates proliferation is unknown. Herein, we validate that knockdown of GREB1 results in growth arrest and that exogenous GREB1 expression initiates oncogene-induced senescence, suggesting that an optimal level of GREB1 expression is necessary for proliferation of breast cancer cells. Under both of these conditions, GREB1 is able to regulate signaling through the PI3K/Akt/mTOR pathway. GREB1 acts intrinsically through PI3K to regulate PIP3 levels and Akt activity. Critically, growth suppression of estrogen-dependent breast cancer cells by GREB1 knockdown is rescued by expression of constitutively activated Akt. Together, these data identify a novel molecular function by which GREB1 regulates breast cancer proliferation through Akt activation and provides a mechanistic link between estrogen signaling and the PI3K pathway.

scholarly journals GREB1 regulates PI3K/Akt signaling to control hormone-sensitive breast cancer proliferation

2020 ◽  
Author(s):  
Corinne N Haines ◽  
Hope D Klingensmith ◽  
Makanko Komara ◽  
Craig J Burd
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Growth Regulation ◽  
Mtor Pathway ◽  
Estrogen Signaling ◽  
Molecular Function ◽  
Breast Cancers ◽  
Cancer Proliferation ◽  
Gene Target

Abstract Over 70% of breast cancers express the estrogen receptor (ER) and depend on ER activity for survival and proliferation. While hormone therapies that target receptor activity are initially effective, patients invariably develop resistance which is often associated with activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. While the mechanism by which estrogen regulates proliferation is not fully understood, one gene target of ER, growth regulation by estrogen in breast cancer 1 (GREB1), is required for hormone-dependent proliferation. However, the molecular function by which GREB1 regulates proliferation is unknown. Herein, we validate that knockdown of GREB1 results in growth arrest and that exogenous GREB1 expression initiates senescence, suggesting that an optimal level of GREB1 expression is necessary for proliferation of breast cancer cells. Under both of these conditions, GREB1 is able to regulate signaling through the PI3K/Akt/mTOR pathway. GREB1 acts intrinsically through PI3K to regulate phosphatidylinositol (3,4,5)-triphosphate levels and Akt activity. Critically, growth suppression of estrogen-dependent breast cancer cells by GREB1 knockdown is rescued by expression of constitutively activated Akt. Together, these data identify a novel molecular function by which GREB1 regulates breast cancer proliferation through Akt activation and provides a mechanistic link between estrogen signaling and the PI3K pathway.

scholarly journals PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 623
Author(s):  
Marit Rasmussen ◽  
Susanna Tan ◽  
Venkata S. Somisetty ◽  
David Hutin ◽  
Ninni Elise Olafsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Modification ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Adp Ribosylation ◽  
Protein Levels ◽  
17Β Estradiol ◽  
Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

scholarly journals TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2340
Author(s):  
Angelina T. Regua ◽  
Noah R. Aguayo ◽  
Sara Abu Jalboush ◽  
Daniel L. Doheny ◽  
Sara G. Manore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Gene Transcription ◽  
Target Genes ◽  
Triple Negative ◽  
Breast Cancer Stem Cells ◽  
Breast Cancers ◽  
Co Activation ◽  
Stat3 Phosphorylation

JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched 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.

scholarly journals The West Midlands breast cancer screening status algorithm – methodology and use as an audit tool

2005 ◽  
Vol 12 (4) ◽  
pp. 179-184 ◽  
Author(s):  
Gill Lawrence ◽  
Olive Kearins ◽  
Emma O'Sullivan ◽  
Nancy Tappenden ◽  
Matthew Wallis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Screening ◽  
Screening Programme ◽  
Breast Cancers ◽  
Audit Tool ◽  
The West ◽  
Breast Screening Programme ◽  
Multiple Primaries ◽  
West Midlands ◽  
Malignant Breast

Objectives: To illustrate the ability of the West Midlands breast screening status algorithm to assign a screening status to women with malignant breast cancer, and its uses as a quality assurance and audit tool. Methods: Breast cancers diagnosed between the introduction of the National Health Service [NHS] Breast Screening Programme and 31 March 2001 were obtained from the West Midlands Cancer Intelligence Unit (WMCIU). Screen-detected tumours were identified via breast screening units, and the remaining cancers were assigned to one of eight screening status categories. Multiple primaries and recurrences were excluded. Results: A screening status was assigned to 14,680 women (96% of the cohort examined), 110 cancers were not registered at the WMCIU and the cohort included 120 screen-detected recurrences. Conclusions: The West Midlands breast screening status algorithm is a robust simple tool which can be used to derive data to evaluate the efficacy and impact of the NHS Breast Screening Programme.

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 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 ER-Negative Breast Cancer Is Highly Responsive to Cholesterol Metabolite Signalling

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2618 ◽  
Author(s):  
Samantha A Hutchinson ◽  
Priscilia Lianto ◽  
Hanne Roberg-Larsen ◽  
Sebastiano Battaglia ◽  
Thomas A Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Target Genes ◽  
Cholesterol Metabolism ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Hormone Receptor Positive ◽  
Er Positive ◽  
Positive Breast Cancer

Interventions that alter cholesterol have differential impacts on hormone receptor positive- and negative-breast cancer risk and prognosis. This implies differential regulation or response to cholesterol within different breast cancer subtypes. We evaluated differences in side-chain hydroxycholesterol and liver X nuclear receptor signalling between Oestrogen Receptor (ER)-positive and ER-negative breast cancers and cell lines. Cell line models of ER-positive and ER-negative disease were treated with Liver X Receptor (LXR) ligands and transcriptional activity assessed using luciferase reporters, qPCR and MTT. Publicly available datasets were mined to identify differences between ER-negative and ER-positive tumours and siRNA was used to suppress candidate regulators. Compared to ER-positive breast cancer, ER-negative breast cancer cells were highly responsive to LXR agonists. In primary disease and cell lines LXRA expression was strongly correlated with its target genes in ER-negative but not ER-positive disease. Expression of LXR’s corepressors (NCOR1, NCOR2 and LCOR) was significantly higher in ER-positive disease relative to ER-negative, and their knock-down equalized sensitivity to ligand between subtypes in reporter, gene expression and viability assays. Our data support further evaluation of dietary and pharmacological targeting of cholesterol metabolism as an adjunct to existing therapies for ER-negative and ER-positive breast cancer patients.

scholarly journals Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

2016 ◽  
Vol 2 (6) ◽  
pp. e1501924 ◽  
Author(s):  
Hari Singhal ◽  
Marianne E. Greene ◽  
Gerard Tarulli ◽  
Allison L. Zarnke ◽  
Ryan J. Bourgo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Tumor Regression ◽  
Progesterone Receptors ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Estrogen Action ◽  
Cellular Processes ◽  
Estrogen Receptor Positive ◽  
Estrogen Antagonist

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored.

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