Deregulation of the phosphatase, PP2A is a common event in breast cancer, predicting sensitivity to FTY720

Baldacchino, Shawn; Saliba, Christian; Petroni, Vanessa; Fenech, Anthony G.; Borg, Nigel; Grech, Godfrey

doi:10.1186/1878-5085-5-3

Cited by 40 publications

(38 citation statements)

References 54 publications

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“…Depending upon the physiological requirements of the cell, proteins transiently shift from a phosphorylated to a dephosphorylated state, with the balance controlled by protein kinases and phosphatases (30,31). PP2A, a serine/threonine protein phosphatase, has been previously suggested to be a tumor suppressor protein in AIs-resistant ER-positive breast cancer cells (17,28,32). In the present study, PP2A tumor suppressor activity was first observed upon treatment with OA, a selective but not specific inhibitor of PP2A, which potently promoted resistance to E 2 deprivation in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 57%

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Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

et al. 2017

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Abstract. Aromatase inhibitors (AIs) are effective endocrine therapeutics for postmenopausal women with estrogen receptor (ER)α-positive breast cancer. However, the efficacy of the treatment is often limited by the onset of AI resistance, owing to the phosphorylation of ERα serine 167 (Ser167). Previous studies have indicated that hyperactivation of the phosphoinositide-3 kinase/RAC serine/threonine-protein kinase signaling pathway occurs in AI-resistant breast cancer models, which coincides with elevated levels of ERα phosphorylation at Ser167. The tumor suppressor serine/threonine-protein phosphatase 2A (PP2A) regulates the phosphatidylinositol 3-kinase/RAC serine/threonine-protein kinase signaling pathway. A previous study indicated that PP2A inhibition decreased ERα Ser167 phosphorylation and estradiol (E 2 )-independent cell growth. The present study investigated the potential relevance of PP2A in E 2 deprivation-resistant MCF-7 cells. E 2 depletion reduced the susceptibility of MCF-7 cells to inhibitors of mechanistic target of rapamycin (mTOR) and significantly increased ERα Ser167 phosphorylation and decreased expression of PP2A. Conversely, long-term E 2 -deprived (LTED) MCF-7 cells, a model of AI-resistant breast cancer, exhibited decreased ERα Ser167 phosphorylation and further upregulation of PP2A in E 2 -containing medium. The PP2A activator forskolin (FSK) significantly inhibited LTED cell proliferation by increasing the effect of everolimus (Eve), an mTOR inhibitor. In summary, the present study provides further evidence that PP2A represents a therapeutic target for AI-resistant breast cancer.

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Section: Discussionmentioning

confidence: 57%

“…PP2A is involved in endocrine therapy resistance (28). Therefore, MCF-7 cells cultured without steroids were examined after 1 or 5 days, which activated mTOR.…”

Section: E 2 Deprivation Reduces Pp2a Levels In Mcf-7 Cellsmentioning

confidence: 99%

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

et al. 2017

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“…In addition, molecular classification into therapeutic groups shall provide a better understanding of actionable pharmacogenetic biomarkers [17], and potentially targeting new proteins for better treatment [18]. The proper use of biomarkers and the utilization of archival material, with readily available clinical outcome data, provides proper implementation of personalised medicine [19].…”

Section: Discussionmentioning

confidence: 99%

Molecular Classification of Breast Cancer Patients Using Formalin-fixed Paraffin-embedded Derived RNA Samples

Grech¹,

Baldacchino²

2016

J Mol Biomark Diagn

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The use of archival formalin-fixed paraffin-embedded (FFPE) material to analyse gene expression is limited by the low quality of extracted RNA. In this paper, we utilised an RNA based assay to quantify expression of luminal and basal markers, together with ERBB2 probes, in FFPE archival tissue from 2009 to 2010, all of which had clinical and therapeutic information of more than 5 years. Receptor status of the patients was characterised using the QuantiGene® Plex assay with 100% concordance to immunohistochemical (IHC) and fluorescence in situ hybridisation (FISH) results. A panel of molecular markers known to classify luminal and basal tumours were used and correlated with receptor status of the tumours. As expected, the triple negative breast cancer (TNBC) samples were classified as basal and oestrogen receptor (ER) positive cases as luminal. In summary, the QuantiGene® Plex technology provides a platform to quantitate novel panels of biomarkers on archival material. Moreover, multiplex analysis allows the use of minimal amounts of material providing an opportunity to utilise laser micro-dissected material. FFPE tissue samples are an invaluable resource for retrospective studies to interrogate current novel biomarkers, particularly to generate disease free survival and overall survival graphs to measure predictive value using well annotated retrospective samples with full clinical and pharmacological outcomes.

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“…9,11,18 Of note, CIP2A is weakly expressed in normal breast tissue as protein and transcript. 7,15 Similar to the study of Tseng et al (2012) 37 and Choi et al, 38 in this study the H-score was used to obtain more information on the distribution of CIP2A scores and intensities.…”

Section: Discussionmentioning

confidence: 99%

“…Amplification/gain of CIP2A as well as overexpression of CIP2A is fairly common across various tumour types. [9][10][11] Various studies have associated higher CIP2A expression with grade, highly proliferative tumours, and stage in distinct tumour types such as prostate, gastric, colon, breast, head and neck squamous cell carcinoma, and ovarian cancer. 7,9,[12][13][14][15][16][17] Our interest in CIP2A stems from its inhibitory activity on protein phosphatase 2A (PP2A), which results in protection of MYC from dephosphorylation thereby stabilising the oncogenic stimulation of MYC on cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

et al. 2017

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CIP2A is emerging as an oncoprotein overexpressed commonly across many tumours and generally correlated with higher tumour grade and therapeutic resistance. CIP2A drives an oncogenic potential through inhibiting protein phosphatase 2A, stabilizing MYC, and promoting epithelial-to-mesenchymal transition, although further biological mechanisms for CIP2A are yet to be defined. CIP2A protein expression was studied by immunohistochemistry in oestrogen receptor-positive primary breast cancers (n = 250) obtained from the Leeds Tissue Bank. In total, 51 cases presented with a relapse or metastasis during adjuvant treatment with tamoxifen and were regarded as tamoxifen resistant. CIP2A expression was scored separately for cytoplasmic, nuclear, or membranous staining, and scores were tested for statistically significant relationships with clinicopathological features. Membranous CIP2A was preferentially expressed in cases who experienced a recurrence during tamoxifen treatment thus predicting a worse overall survival (log rank = 8.357, p = 0.004) and disease-free survival (log rank = 21.766, p < 0.001). Cox multivariate analysis indicates that it is an independent prognostic indicator for overall survival (hazard ratio = 4.310, p = 0.013) and disease-free survival (hazard ratio = 5.449, p = 0.002). In this study, we propose the assessment of membranous CIP2A expression as a potential novel prognostic and predictive indicator for tamoxifen resistance and recurrence within oestrogen receptor-positive breast cancer.

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Deregulation of the phosphatase, PP2A is a common event in breast cancer, predicting sensitivity to FTY720

Cited by 40 publications

References 54 publications

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

Estradiol suppresses phosphorylation of ERα serine 167 through upregulation of PP2A in breast cancer cells

Molecular Classification of Breast Cancer Patients Using Formalin-fixed Paraffin-embedded Derived RNA Samples

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

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