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

Publication ,  Journal Article
Mazumdar, A; Poage, GM; Shepherd, J; Tsimelzon, A; Hartman, ZC; Den Hollander, P; Hill, J; Zhang, Y; Chang, J; Hilsenbeck, SG; Fuqua, S ...
Published in: Breast Cancer Res Treat
August 2016

Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-negative" breast cancer (TNBC). Because phosphatases regulate the function of kinase signaling pathways, in this study, we investigated whether phosphatases are also differentially expressed in ER-negative compared to those in ER-positive breast cancers. We compared RNA expression in 98 human breast cancers (56 ER-positive and 42 ER-negative) to identify phosphatases differentially expressed in ER-negative compared to those in ER-positive breast cancers. We then examined the effects of one selected phosphatase, dual specificity phosphatase 4 (DUSP4), on proliferation, cell growth, migration and invasion, and on signaling pathways using protein microarray analyses of 172 proteins, including phosphoproteins. We identified 48 phosphatase genes are significantly differentially expressed in ER-negative compared to those in ER-positive breast tumors. We discovered that 31 phosphatases were more highly expressed, while 11 were underexpressed specifically in ER-negative breast cancers. The DUSP4 gene is underexpressed in ER-negative breast cancer and is deleted in approximately 50 % of breast cancers. Induced DUSP4 expression suppresses both in vitro and in vivo growths of breast cancer cells. Our studies show that induced DUSP4 expression blocks the cell cycle at the G1/S checkpoint; inhibits ERK1/2, p38, JNK1, RB, and NFkB p65 phosphorylation; and inhibits invasiveness of TNBC cells. These results suggest that that DUSP4 is a critical regulator of the growth and invasion of triple-negative breast cancer cells.

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Published In

Breast Cancer Res Treat

DOI

EISSN

1573-7217

Publication Date

August 2016

Volume

158

Issue

3

Start / End Page

441 / 454

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Receptors, Estrogen
  • Protein Array Analysis
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Neoplasm Invasiveness
  • Mitogen-Activated Protein Kinase Phosphatases
  • Mice
  • MCF-7 Cells
 

Citation

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Mazumdar, A., Poage, G. M., Shepherd, J., Tsimelzon, A., Hartman, Z. C., Den Hollander, P., … Brown, P. H. (2016). Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast Cancer Res Treat, 158(3), 441–454. https://doi.org/10.1007/s10549-016-3892-y
Mazumdar, Abhijit, Graham M. Poage, Jonathan Shepherd, Anna Tsimelzon, Zachary C. Hartman, Petra Den Hollander, Jamal Hill, et al. “Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.Breast Cancer Res Treat 158, no. 3 (August 2016): 441–54. https://doi.org/10.1007/s10549-016-3892-y.
Mazumdar A, Poage GM, Shepherd J, Tsimelzon A, Hartman ZC, Den Hollander P, et al. Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast Cancer Res Treat. 2016 Aug;158(3):441–54.
Mazumdar, Abhijit, et al. “Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.Breast Cancer Res Treat, vol. 158, no. 3, Aug. 2016, pp. 441–54. Pubmed, doi:10.1007/s10549-016-3892-y.
Mazumdar A, Poage GM, Shepherd J, Tsimelzon A, Hartman ZC, Den Hollander P, Hill J, Zhang Y, Chang J, Hilsenbeck SG, Fuqua S, Kent Osborne C, Mills GB, Brown PH. Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. Breast Cancer Res Treat. 2016 Aug;158(3):441–454.
Journal cover image

Published In

Breast Cancer Res Treat

DOI

EISSN

1573-7217

Publication Date

August 2016

Volume

158

Issue

3

Start / End Page

441 / 454

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Receptors, Estrogen
  • Protein Array Analysis
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Neoplasm Invasiveness
  • Mitogen-Activated Protein Kinase Phosphatases
  • Mice
  • MCF-7 Cells