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

Abstract

BackgroundThe most commonly used biomarkers to predict the response of breast cancer patients to therapy are the oestrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). Patients positive for these biomarkers are eligible for specific therapies such as endocrine treatment in the event of ER and PgR positivity, and the monoclonal antibody, trastuzumab, in the case of HER2-positive patients. Patients who are negative for these three biomarkers, the so-called triple negatives, however, derive little benefit from such therapies and are associated with a worse prognosis. Deregulation of the protein serine/threonine phosphatase type 2A (PP2A) and its regulatory subunits is a common event in breast cancer, providing a possible target for therapy.MethodsThe data portal, cBioPortal for Cancer Genomics was used to investigate the incidence of conditions that are associated with low phosphatase activity. Four (4) adherent human breast cancer cell lines, MDA-MB-468, MDA-MB-436, Hs578T and BT-20 were cultured to assess their viability when exposed to various dosages of rapamycin or FTY720. In addition, RNA was extracted and cDNA was synthesised to amplify the coding sequence of PPP2CA. Amplification was followed by high-resolution melting to identify variations.Results and conclusionThe sequence of PPP2CA was found to be conserved across a diverse panel of solid tumour and haematological cell lines, suggesting that low expression of PPP2CA and differential binding of inhibitory PPP2CA regulators are the main mechanisms of PP2A deregulation. Interestingly, the cBioPortal for Cancer Genomics shows that PP2A is deregulated in 59.6% of basal breast tumours. Viability assays performed to determine the sensitivity of a panel of breast cancer cell lines to FTY720, a PP2A activator, indicated that cell lines associated with ER loss are sensitive to lower doses of FTY720. The subset of patients with suppressed PP2A activity is potentially eligible for treatment using therapies which target the PI3K/AKT/mTOR pathway, such as phosphatase activators.

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

“…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.…”

“…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.…”

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

“…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].…”

CIP2A expression predicts recurrences of tamoxifen-treated breast cancer

“…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.…”

“…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.…”