Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression

Abstract

BackgroundTriple-negative breast cancer (TNBC) remains difficult to be targeted. SET and cancerous inhibitor of protein phosphatase 2A (CIP2A) are intrinsic protein-interacting inhibitors of protein phosphatase 2A (PP2A) and frequently overexpressed in cancers, whereas reactivating PP2A activity has been postulated as an anti-cancer strategy. Here we explored this strategy in TNBC.MethodsData from The Cancer Genome Atlas (TCGA) database was analyzed. TNBC cell lines were used for in vitro studies. Cell viability was examined by MTT assay. The apoptotic cells were examined by flow cytometry and Western blot. A SET-PP2A protein-protein interaction antagonist TD19 was used to disrupt signal transduction. In vivo efficacy of TD19 was tested in MDA-MB-468-xenografted animal model.FindingsTCGA data revealed upregulation of SET and CIP2A and positive correlation of these two gene expressions in TNBC tumors. Ectopic SET or CIP2A increased cell viability, migration, and invasion of TNBC cells. Notably ERK inhibition increased PP2A activity. ERK activation is known crucial for Elk-1 activity, a transcriptional factor regulating CIP2A expression, we hypothesized an oncogenic feedforward loop consisting of pERK/pElk-1/CIP2A/PP2A. This loop was validated by knockdown of PP2A and ectopic expression of Elk-1, showing reciprocal changes in loop members. In addition, ectopic expression of SET increased pAkt, pERK, pElk-1 and CIP2A expressions, suggesting a positive linkage between SET and CIP2A signaling. Moreover, TD19 disrupted this CIP2A-feedforward loop by restoring PP2A activity, demonstrating in vitro and in vivo anti-cancer activity. Mechanistically, TD19 downregulated CIP2A mRNA via inhibiting pERK-mediated Elk-1 nuclear translocation thereby decreased Elk-1 binding to the CIP2A promoter.InterpretationThese findings suggested that a novel oncogenic CIP2A-feedforward loop contributes to TNBC progression and targeting SET to disrupt this oncogenic CIP2A loop showed therapeutic potential in TNBC.

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

“…Consistent with the tumor suppressor role of PP2A, the PP2A inhibitors, inhibitor-2 of protein phosphatase-2A (SET) and cancerous inhibitor of PP2A (CIP2A), are overexpressed in a variety of cancers [122][123][124][125][126]. These proteins function to prevent PP2A-B subunits from binding the PP2A A-C core complex, decreasing global PP2A activity and contributing to therapeutic resistance [127,128].…”

Role of Protein Phosphatase-2A (PP-2A) in the Control of Mitosis and Meiosis.

“…The authors of the Dupre et al [5], Lemmonier et al [9] and Dupre et al [139] completely ignored published works that contradicted their work and did not provide any reasons to the readers and Scientific Researchers who are trying to decipher who is/are telling the truth and whether to spend resources in man hours to try to repeat their published works that are at best misleading and at worse dishonest. The idea that a form of PP-2A could undergo marked inhibition during resumption of meiosis is not compatible with the known function of PP-2A as a key controller of cell transformation and as tumor suppressor [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100].…”

“…One or more form(s) of PP-2A in the cell has/have low basal activity upon entry into mitosis and becomes moderately activated prior to and exit of mitosis. As countless studies have shown, logically, extensive inhibition of PP2A would lead to cell transformation and tumorigenesis[85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100].The following model for the role of PP-1 and PP-2A in the control of mitosis that does not rest upon the conclusions of Mochida et al[1] and Gharbi-Ayashi et al[2] are a lot more realistic. The model takes in account the works of Mayer-Jackel et al[24,25], Hutchins et al[26], Peng et al[101,102], Margolis et al[27,115,116], Forrester et al[28], Wu et al[117], Tung et al[110,111,156], Puntoni and Villa-Moruzzi[152,153], Dohadwala et al[161], Kwon et al[162], Lamb et al[165], Brautigan et al[166], Fernandez et al[167], and Li et al[160], Model for the role of PP-2A in the control of meiosis.Role of PP-2A in the control of meiosis in Xenopus oocytes.…”

Deregulation of Protein Phosphatase 2A inhibitor SET is Associated with Malignant Progression in Breast Cancer

“…In addition, the majority of the CIP2Aand PME-1-target peptides overlapped with the target peptides of SET 22 . Furthermore, targeting of SET with siRNA also down-regulates CIP2A 23 . Therefore, we hypothesised that SET might be the desired target molecule, if it is expressed in CTCs.…”