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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2016

Open Access 01-08-2016 | Preclinical study

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

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

Published in: Breast Cancer Research and Treatment | Issue 3/2016

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Abstract

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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Metadata
Title
Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion
Authors
Abhijit Mazumdar
Graham M. Poage
Jonathan Shepherd
Anna Tsimelzon
Zachary C. Hartman
Petra Den Hollander
Jamal Hill
Yun Zhang
Jenny Chang
Susan G. Hilsenbeck
Suzanne Fuqua
C. Kent Osborne
Gordon B. Mills
Powel H. Brown
Publication date
01-08-2016
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2016
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-016-3892-y

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