Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion

Mazumdar, Abhijit; Poage, Graham M.; Shepherd, Jonathan H.; Tsimelzon, Anna; Hartman, Zachary C.; Hollander, Petra den; Hill, Jamal; Zhang, Yun; Chang, Jenny C.; Hilsenbeck, Susan G.; Fuqua, Suzanne A.W.; Osborne, C. Kent; Mills, Gordon B.; Brown, Powel H.

doi:10.1007/s10549-016-3892-y

Cited by 27 publications

(29 citation statements)

References 53 publications

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“…It has recently been demonstrated that in physiologic conditions, the activation of MAPK promotes DUSP4 expression, which in turn suppresses ERK, ensuring breast cell turnover. Nevertheless, loss of DUSP4 and its methylation lead to an aberrant cell proliferation in basal-like breast cancers (9,10). In addition, the activation of NF-kB signaling plays a crucial role in downregulating the expression levels of DUSP4 in endothelial cells (46).…”

Section: Discussionmentioning

confidence: 99%

“…9). In physiologic conditions, the transcription of DUSP4 is MEK-dependent and its expression in turn suppresses ERK, along with p38, JNK1, NF-kB, and Rb (9)(10)(11)(12), ensuring a proper negative feedback control of cellular proliferative stimuli. DUSP4 is differentially expressed among luminal and basal breast cancers.…”

Section: Introductionmentioning

confidence: 99%

“…DUSP4 is differentially expressed among luminal and basal breast cancers. Specifically, the most aggressive tumors hold DUSP4 under-expression, due to methylation events or genomic loss (9,10).…”

Section: Introductionmentioning

confidence: 99%

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IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

et al. 2017

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The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptorpositive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Ra antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

et al. 2017

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“…Loss of DEP1 is associated with increased growth factor receptor signaling and promotes cell growth (12). Recently, Mazumdar et al identified dual specificity phosphatase 4 (DUSP4) as the most commonly underexpressed protein phosphatase in ER-negative breast cancers, and showed that ectopic expression of DUSP4 inhibits the growth and invasive properties of ER-negative breast cancer cells by dephosphorylating growth promoting signaling proteins (13). Similarly, loss of DUSP4 promotes the progression of intraepithelial neoplasms into invasive carcinoma in the pancreas (14).…”

Section: Phosphatases As Tumor Suppressorsmentioning

confidence: 99%

Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer

Bollu

Mazumdar

Savage

et al. 2017

Clinical Cancer Research

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114

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The aberrant activation of oncogenic signaling pathways is a universal phenomenon in cancer and drives tumorigenesis and malignant transformation. This abnormal activation of signaling pathways in cancer is due to the altered expression of protein kinases and phosphatases. In response to extra cellular signals, protein kinases activate downstream signaling pathways through a series of protein phosphorylation events, ultimately producing a signal response. Protein tyrosine phosphatases (PTPs) are a family of enzymes that hydrolytically remove phosphate groups from proteins. Initially, PTPs were shown to act as tumor suppressor genes by terminating signal responses through the dephosphorylation of oncogenic kinases. More recently, it has become clear that several PTPs overexpressed in human cancers do not suppress tumor growth; instead, they positively regulate signaling pathways and promote tumor development and progression. In this review, we discuss both types of PTPs; those that have tumor suppressor activities, as well as those that act as oncogene. We also discuss the potential of PTP inhibitors for cancer therapy.

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“…Ligand-dependent activation of EGFR represents the critical first step of the transcriptional programs regulated by the MEK/ERK pathway, provided that the tumors lack genetic alterations in pathway components that would render the pathway constitutively active. While activating mutations in the EGFR/RAS/RAF/MEK/ERK pathway are rare in breast cancer, approximately 50% of TNBCs are characterized by hemi- or homozygous deletion of the DUSP4 gene, which leads to aberrant pathway activation [24, 28, 29]. Thus, TNBCs harboring DUSP4 genomic loss should be less dependent on EGFR activation.…”

Section: Introductionmentioning

confidence: 99%

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Wise

Żółkiewska

2017

Breast Cancer Res Treat

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Purpose The CD44+/CD24− cell phenotype is enriched in triple negative breast cancers (TNBCs), is associated with tumor invasive properties, and serves as a cell surface marker profile of breast cancer stem-like cells. Activation of Epidermal Growth Factor Receptor (EGFR) promotes the CD44+/CD24− phenotype, but the specific signaling pathway downstream of EGFR responsible for this effect is not clear. The purpose of this study was to determine the role of the MEK/ERK pathway in the expansion of CD44+/CD24− populations in TNBC cells in response to EGFR activation. Methods Representative TNBC cell lines SUM159PT (claudin-low) and SUM149PT (basal) were used to evaluate cell surface expression of CD44 and CD24 by flow cytometry in response to EGFR and MEK inhibition or activation. EGFR and ERK phosphorylation levels were analyzed by Western blotting. The relationship between EGFR phosphorylation and MEK activation score in basal and claudin-low tumors from the TCGA database was examined. Results Inhibition of ERK activation with selumetinib, a MEK1/2 inhibitor, blocked EGF-induced expansion of CD44+/CD24− populations. Sustained activation of ERK by overexpression of constitutively active MEK1 was sufficient to expand CD44+/CD24− populations in cells in which EGFR activity was blocked by either erlotinib, an EGFR kinase inhibitor, or BB-94, a metalloprotease inhibitor that prevents generation of soluble EGFR ligands. In basal and claudin-low tumors from the TCGA database, there was a positive correlation between EGFR_pY1068 and MEK activation score in tumors without genomic loss of DUSP4, a negative regulator of ERK, but not in tumors harboring DUSP4 deletion. Conclusion Our results demonstrate that ERK activation is a key event in EGFR-dependent regulation of CD44+/CD24− populations. Furthermore, our findings highlight the role of ligand-mediated EGFR signaling in the control of MEK/ERK pathway output in TNBC tumors without DUSP4 loss.

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Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion

Cited by 27 publications

References 53 publications

IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

Molecular Pathways: Targeting Protein Tyrosine Phosphatases in Cancer

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

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