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Phosphoproteome profiling reveals critical role of JAK-STAT signaling in maintaining chemoresistance in breast cancer.

ABSTRACT: Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MCF7Res cells to chemotherapy-sensitive MCF cells using a peptide array approach that provides an atlas of cellular kinase activities and consequently, predominant pathways can be identified. We observed that peptides phosphorylated by elements of JAK-STAT signaling pathway and PKC signaling pathways are subject to extensive kinase activity in MCF7Res cells as compared to chemotherapy-sensitive MCF cells; and Western blotting confirmed relatively strong activation of these signaling pathways in chemoresistant cells. Importantly, treatment of cells with Tofacitinib, a FDA-approved JAK inhibitor, converted chemoresistant cells to chemosensitive cells, inducing apoptosis when used in conjunction with doxorubicin. Thus our results reveal that chemoresistance in breast cancer is associated with activation of JAK/STAT signaling and suggest that JAK2 may be useful for combating chemoresistance in breast cancer.

SUBMITTER: Nascimento AS

PROVIDER: S-EPMC5777730 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Phosphoproteome profiling reveals critical role of JAK-STAT signaling in maintaining chemoresistance in breast cancer.

Nascimento Augusto S AS Peres Luisa L LL Fari Alessandra V S AVS Milani Renato R Silva Rodrigo A RA da Costa Fernandes Celio Jr CJ Peppelenbosch Maikel P MP Ferreira-Halder Carmen V CV Zambuzzi Willian F WF

Oncotarget 20171010 70

Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MC ...[more]

PMID: 29383118

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Project description:Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.SignificanceChemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.

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Phosphoproteome profiling reveals critical role of JAK-STAT signaling in maintaining chemoresistance in breast cancer.

Publications

Phosphoproteome profiling reveals critical role of JAK-STAT signaling in maintaining chemoresistance in breast cancer.

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