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

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 Mills, Powel H. Brown

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)441-454
Number of pages14
JournalBreast Cancer Research and Treatment
Volume158
Issue number3
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Fingerprint

Dual-Specificity Phosphatases
Phosphoric Monoester Hydrolases
Estrogen Receptors
Breast Neoplasms
Growth
Triple Negative Breast Neoplasms
Phosphotransferases
Protein Array Analysis
Phosphoproteins
Progesterone Receptors
Genes

Keywords

  • MAPK pathways
  • Mouse xenograft
  • Phosphatase
  • TNBC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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 Research and Treatment, 158(3), 441-454. https://doi.org/10.1007/s10549-016-3892-y

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; Tsimelzon, Anna; Hartman, Zachary C.; Den Hollander, Petra; Hill, Jamal; Zhang, Yun; Chang, Jenny; Hilsenbeck, Susan G.; Fuqua, Suzanne; Kent Osborne, C.; Mills, Gordon; Brown, Powel H.

In: Breast Cancer Research and Treatment, Vol. 158, No. 3, 01.08.2016, p. 441-454.

Research output: Contribution to journalArticle

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, G & Brown, PH 2016, 'Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion', Breast Cancer Research and Treatment, vol. 158, no. 3, pp. 441-454. https://doi.org/10.1007/s10549-016-3892-y
Mazumdar, Abhijit ; Poage, Graham M. ; Shepherd, Jonathan ; Tsimelzon, Anna ; Hartman, Zachary C. ; Den Hollander, Petra ; Hill, Jamal ; Zhang, Yun ; Chang, Jenny ; Hilsenbeck, Susan G. ; Fuqua, Suzanne ; Kent Osborne, C. ; Mills, Gordon ; Brown, Powel H. / Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion. In: Breast Cancer Research and Treatment. 2016 ; Vol. 158, No. 3. pp. 441-454.
@article{13a9792a9f7c4fb586e31a5eba3eed9b,
title = "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.",
keywords = "MAPK pathways, Mouse xenograft, Phosphatase, TNBC",
author = "Abhijit Mazumdar and Poage, {Graham M.} and Jonathan Shepherd and Anna Tsimelzon and Hartman, {Zachary C.} and {Den Hollander}, Petra and Jamal Hill and Yun Zhang and Jenny Chang and Hilsenbeck, {Susan G.} and Suzanne Fuqua and {Kent Osborne}, C. and Gordon Mills and Brown, {Powel H.}",
year = "2016",
month = "8",
day = "1",
doi = "10.1007/s10549-016-3892-y",
language = "English (US)",
volume = "158",
pages = "441--454",
journal = "Breast Cancer Research and Treatment",
issn = "0167-6806",
publisher = "Springer New York",
number = "3",

}

TY - JOUR

T1 - Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion

AU - Mazumdar, Abhijit

AU - Poage, Graham M.

AU - Shepherd, Jonathan

AU - Tsimelzon, Anna

AU - Hartman, Zachary C.

AU - Den Hollander, Petra

AU - Hill, Jamal

AU - Zhang, Yun

AU - Chang, Jenny

AU - Hilsenbeck, Susan G.

AU - Fuqua, Suzanne

AU - Kent Osborne, C.

AU - Mills, Gordon

AU - Brown, Powel H.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

KW - MAPK pathways

KW - Mouse xenograft

KW - Phosphatase

KW - TNBC

UR - http://www.scopus.com/inward/record.url?scp=84978160926&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978160926&partnerID=8YFLogxK

U2 - 10.1007/s10549-016-3892-y

DO - 10.1007/s10549-016-3892-y

M3 - Article

VL - 158

SP - 441

EP - 454

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 3

ER -