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

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.

• 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
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 158 Issue 3 Pg. 441-54 (08 2016) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 27393618 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Receptors, Estrogen
• Mitogen-Activated Protein Kinase Phosphatases
• DUSP4 protein, human
• Dual-Specificity Phosphatases

Topics

• Animals
• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Down-Regulation
• Dual-Specificity Phosphatases (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Mice
• Mitogen-Activated Protein Kinase Phosphatases (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Phosphorylation
• Protein Array Analysis (methods)
• Receptors, Estrogen (deficiency, metabolism)
• Signal Transduction