Department of Pathology, Medical School, University of Malta, Msida MSD2090, Malta.
Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida MSD2090, Malta.
EPMA J. 2014 Jan 25;5(1):3. doi: 10.1186/1878-5085-5-3.
The 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.
The 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.
The 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.
目前，预测乳腺癌患者对治疗反应的最常用生物标志物是雌激素受体（ER）、孕激素受体（PgR）和人表皮生长因子受体 2（HER2）。这些生物标志物阳性的患者适合接受特定的治疗，例如 ER 和 PgR 阳性患者的内分泌治疗，以及 HER2 阳性患者的曲妥珠单抗单克隆抗体治疗。然而，这些生物标志物均为阴性的患者，即所谓的三阴性患者，从这些治疗中获益甚少，且预后较差。蛋白丝氨酸/苏氨酸磷酸酶 2A（PP2A）及其调节亚基的失活在乳腺癌中较为常见，这为治疗提供了一个可能的靶点。
使用癌症基因组学 cBioPortal 数据门户，调查与低磷酸酶活性相关的情况的发生率。培养 4 株（4 个）贴壁人乳腺癌细胞系 MDA-MB-468、MDA-MB-436、Hs578T 和 BT-20，以评估它们在暴露于不同剂量雷帕霉素或 FTY720 时的活力。此外，提取 RNA 并合成 cDNA 以扩增 PPP2CA 的编码序列。扩增后进行高分辨率熔解以识别变体。
发现 PPP2CA 的序列在各种实体瘤和血液细胞系中是保守的，这表明 PPP2CA 的低表达和抑制性 PPP2CA 调节剂的差异结合是 PP2A 失活的主要机制。有趣的是，癌症基因组学 cBioPortal 显示，PP2A 在 59.6%的基底乳腺癌中失调。为了确定一组乳腺癌细胞系对 PP2A 激活剂 FTY720 的敏感性而进行的活力测定表明，与 ER 丢失相关的细胞系对较低剂量的 FTY720 敏感。潜在地，抑制 PP2A 活性的患者亚组可能有资格接受针对 PI3K/AKT/mTOR 途径的治疗，例如使用磷酸酶激活剂。
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