P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis

Peter R. McHenry, James C. Sears, Matthew P. Herrick, Peggy Chang, Brandy M. Heckman-Stoddard, Megan Rybarczyk, Lewis A. Chodosh, Edward J. Gunther, Susan G. Hilsenbeck, Jeffrey M. Rosen, Tracy Vargo-Gogola

Research output: Contribution to journalArticle

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Abstract

Introduction: Rho GTPases are overexpressed and hyperactivated in human breast cancers. Deficiency of p190B RhoGAP, a major inhibitor of the Rho GTPases, inhibits mouse mammary tumor virus long terminal repeat (MMTV)-Neu/ErbB2 mammary tumor formation and progression in part through effects within the stromal environment, suggesting that p190B function is pro-tumorigenic. To further investigate the potential pro-tumorigenic actions of p190B, we examined the effects of exogenous p190B expression within the mammary epithelium on MMTV-Neu tumor formation and progression.Methods: Tetracycline (tet)-regulatable p190B transgenic mice were bred to MMTV-Neu mice, and the effects of exogenous p190B expression on tumor latency, multiplicity, growth rates, angiogenesis, and metastasis were examined. The effects of exogenous p190B expression on cell-matrix adhesion and invasion were tested using non-transformed primary mammary epithelial cells (MECs). Rho GTPase activity, oxidative stress as an indicator of reactive oxygen species (ROS) production, and downstream signaling pathways were analyzed.Results: Altered p190B expression resulted in a two-fold increase in tumor multiplicity and a three-fold increase in metastases compared to control mice indicating that exogenous p190B expression in the mammary epithelium promotes MMTV-Neu mammary tumor formation and progression. Interestingly, non-transformed primary MECs expressing exogenous p190B displayed increased adhesion to laminin and type IV collagen and formed invasive structures in a three-dimensional culture assay. Ras related C3 botulinum toxin 1 (Rac1)-GTP levels were elevated in p190B transgenic tumors whereas Ras homologous A (RhoA) and cell division cycle 42 (Cdc42)-GTP levels were not significantly altered. Rac1 activity affects production of ROS, which regulate transformation, metastasis, and oxidative stress. Protein carbonylation, which is indicative of oxidative stress, was elevated 1.75-fold in p190B transgenic tumors as compared to control tumors suggesting that exogenous p190B expression may affect Rac1-dependent ROS production.Conclusions: These studies indicate that paradoxically, p190B RhoGAP, a major inhibitor of the Rho GTPases in vitro, has pro-tumorigenic functions that enhance MMTV-Neu induced mammary tumor formation and metastasis. Furthermore, exogenous p190B expression enhances cell adhesion and invasion, which may facilitate metastasis. Rac1 activity and oxidative stress are elevated in tumors expressing exogenous p190B suggesting that p190B may promote tumorigenesis through a Rac1/ROS dependent mechanism.

Original languageEnglish (US)
Article numberR73
JournalBreast Cancer Research
Volume12
Issue number5
DOIs
StatePublished - Sep 22 2010

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Carcinogenesis
Breast
rho GTP-Binding Proteins
Neoplasm Metastasis
Reactive Oxygen Species
Oxidative Stress
Neoplasms
Breast Neoplasms
Guanosine Triphosphate
Epithelium
Epithelial Cells
Protein Carbonylation
Cell-Matrix Junctions
Mouse mammary tumor virus
Collagen Type IV
Botulinum Toxins
Terminal Repeat Sequences
Laminin
Tetracycline
Cell Adhesion

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McHenry, P. R., Sears, J. C., Herrick, M. P., Chang, P., Heckman-Stoddard, B. M., Rybarczyk, M., ... Vargo-Gogola, T. (2010). P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis. Breast Cancer Research, 12(5), [R73]. https://doi.org/10.1186/bcr2643

P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis. / McHenry, Peter R.; Sears, James C.; Herrick, Matthew P.; Chang, Peggy; Heckman-Stoddard, Brandy M.; Rybarczyk, Megan; Chodosh, Lewis A.; Gunther, Edward J.; Hilsenbeck, Susan G.; Rosen, Jeffrey M.; Vargo-Gogola, Tracy.

In: Breast Cancer Research, Vol. 12, No. 5, R73, 22.09.2010.

Research output: Contribution to journalArticle

McHenry, PR, Sears, JC, Herrick, MP, Chang, P, Heckman-Stoddard, BM, Rybarczyk, M, Chodosh, LA, Gunther, EJ, Hilsenbeck, SG, Rosen, JM & Vargo-Gogola, T 2010, 'P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis', Breast Cancer Research, vol. 12, no. 5, R73. https://doi.org/10.1186/bcr2643
McHenry PR, Sears JC, Herrick MP, Chang P, Heckman-Stoddard BM, Rybarczyk M et al. P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis. Breast Cancer Research. 2010 Sep 22;12(5). R73. https://doi.org/10.1186/bcr2643
McHenry, Peter R. ; Sears, James C. ; Herrick, Matthew P. ; Chang, Peggy ; Heckman-Stoddard, Brandy M. ; Rybarczyk, Megan ; Chodosh, Lewis A. ; Gunther, Edward J. ; Hilsenbeck, Susan G. ; Rosen, Jeffrey M. ; Vargo-Gogola, Tracy. / P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis. In: Breast Cancer Research. 2010 ; Vol. 12, No. 5.
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abstract = "Introduction: Rho GTPases are overexpressed and hyperactivated in human breast cancers. Deficiency of p190B RhoGAP, a major inhibitor of the Rho GTPases, inhibits mouse mammary tumor virus long terminal repeat (MMTV)-Neu/ErbB2 mammary tumor formation and progression in part through effects within the stromal environment, suggesting that p190B function is pro-tumorigenic. To further investigate the potential pro-tumorigenic actions of p190B, we examined the effects of exogenous p190B expression within the mammary epithelium on MMTV-Neu tumor formation and progression.Methods: Tetracycline (tet)-regulatable p190B transgenic mice were bred to MMTV-Neu mice, and the effects of exogenous p190B expression on tumor latency, multiplicity, growth rates, angiogenesis, and metastasis were examined. The effects of exogenous p190B expression on cell-matrix adhesion and invasion were tested using non-transformed primary mammary epithelial cells (MECs). Rho GTPase activity, oxidative stress as an indicator of reactive oxygen species (ROS) production, and downstream signaling pathways were analyzed.Results: Altered p190B expression resulted in a two-fold increase in tumor multiplicity and a three-fold increase in metastases compared to control mice indicating that exogenous p190B expression in the mammary epithelium promotes MMTV-Neu mammary tumor formation and progression. Interestingly, non-transformed primary MECs expressing exogenous p190B displayed increased adhesion to laminin and type IV collagen and formed invasive structures in a three-dimensional culture assay. Ras related C3 botulinum toxin 1 (Rac1)-GTP levels were elevated in p190B transgenic tumors whereas Ras homologous A (RhoA) and cell division cycle 42 (Cdc42)-GTP levels were not significantly altered. Rac1 activity affects production of ROS, which regulate transformation, metastasis, and oxidative stress. Protein carbonylation, which is indicative of oxidative stress, was elevated 1.75-fold in p190B transgenic tumors as compared to control tumors suggesting that exogenous p190B expression may affect Rac1-dependent ROS production.Conclusions: These studies indicate that paradoxically, p190B RhoGAP, a major inhibitor of the Rho GTPases in vitro, has pro-tumorigenic functions that enhance MMTV-Neu induced mammary tumor formation and metastasis. Furthermore, exogenous p190B expression enhances cell adhesion and invasion, which may facilitate metastasis. Rac1 activity and oxidative stress are elevated in tumors expressing exogenous p190B suggesting that p190B may promote tumorigenesis through a Rac1/ROS dependent mechanism.",
author = "McHenry, {Peter R.} and Sears, {James C.} and Herrick, {Matthew P.} and Peggy Chang and Heckman-Stoddard, {Brandy M.} and Megan Rybarczyk and Chodosh, {Lewis A.} and Gunther, {Edward J.} and Hilsenbeck, {Susan G.} and Rosen, {Jeffrey M.} and Tracy Vargo-Gogola",
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T1 - P190B RhoGAP has pro-tumorigenic functions during MMTV-Neu mammary tumorigenesis and metastasis

AU - McHenry, Peter R.

AU - Sears, James C.

AU - Herrick, Matthew P.

AU - Chang, Peggy

AU - Heckman-Stoddard, Brandy M.

AU - Rybarczyk, Megan

AU - Chodosh, Lewis A.

AU - Gunther, Edward J.

AU - Hilsenbeck, Susan G.

AU - Rosen, Jeffrey M.

AU - Vargo-Gogola, Tracy

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N2 - Introduction: Rho GTPases are overexpressed and hyperactivated in human breast cancers. Deficiency of p190B RhoGAP, a major inhibitor of the Rho GTPases, inhibits mouse mammary tumor virus long terminal repeat (MMTV)-Neu/ErbB2 mammary tumor formation and progression in part through effects within the stromal environment, suggesting that p190B function is pro-tumorigenic. To further investigate the potential pro-tumorigenic actions of p190B, we examined the effects of exogenous p190B expression within the mammary epithelium on MMTV-Neu tumor formation and progression.Methods: Tetracycline (tet)-regulatable p190B transgenic mice were bred to MMTV-Neu mice, and the effects of exogenous p190B expression on tumor latency, multiplicity, growth rates, angiogenesis, and metastasis were examined. The effects of exogenous p190B expression on cell-matrix adhesion and invasion were tested using non-transformed primary mammary epithelial cells (MECs). Rho GTPase activity, oxidative stress as an indicator of reactive oxygen species (ROS) production, and downstream signaling pathways were analyzed.Results: Altered p190B expression resulted in a two-fold increase in tumor multiplicity and a three-fold increase in metastases compared to control mice indicating that exogenous p190B expression in the mammary epithelium promotes MMTV-Neu mammary tumor formation and progression. Interestingly, non-transformed primary MECs expressing exogenous p190B displayed increased adhesion to laminin and type IV collagen and formed invasive structures in a three-dimensional culture assay. Ras related C3 botulinum toxin 1 (Rac1)-GTP levels were elevated in p190B transgenic tumors whereas Ras homologous A (RhoA) and cell division cycle 42 (Cdc42)-GTP levels were not significantly altered. Rac1 activity affects production of ROS, which regulate transformation, metastasis, and oxidative stress. Protein carbonylation, which is indicative of oxidative stress, was elevated 1.75-fold in p190B transgenic tumors as compared to control tumors suggesting that exogenous p190B expression may affect Rac1-dependent ROS production.Conclusions: These studies indicate that paradoxically, p190B RhoGAP, a major inhibitor of the Rho GTPases in vitro, has pro-tumorigenic functions that enhance MMTV-Neu induced mammary tumor formation and metastasis. Furthermore, exogenous p190B expression enhances cell adhesion and invasion, which may facilitate metastasis. Rac1 activity and oxidative stress are elevated in tumors expressing exogenous p190B suggesting that p190B may promote tumorigenesis through a Rac1/ROS dependent mechanism.

AB - Introduction: Rho GTPases are overexpressed and hyperactivated in human breast cancers. Deficiency of p190B RhoGAP, a major inhibitor of the Rho GTPases, inhibits mouse mammary tumor virus long terminal repeat (MMTV)-Neu/ErbB2 mammary tumor formation and progression in part through effects within the stromal environment, suggesting that p190B function is pro-tumorigenic. To further investigate the potential pro-tumorigenic actions of p190B, we examined the effects of exogenous p190B expression within the mammary epithelium on MMTV-Neu tumor formation and progression.Methods: Tetracycline (tet)-regulatable p190B transgenic mice were bred to MMTV-Neu mice, and the effects of exogenous p190B expression on tumor latency, multiplicity, growth rates, angiogenesis, and metastasis were examined. The effects of exogenous p190B expression on cell-matrix adhesion and invasion were tested using non-transformed primary mammary epithelial cells (MECs). Rho GTPase activity, oxidative stress as an indicator of reactive oxygen species (ROS) production, and downstream signaling pathways were analyzed.Results: Altered p190B expression resulted in a two-fold increase in tumor multiplicity and a three-fold increase in metastases compared to control mice indicating that exogenous p190B expression in the mammary epithelium promotes MMTV-Neu mammary tumor formation and progression. Interestingly, non-transformed primary MECs expressing exogenous p190B displayed increased adhesion to laminin and type IV collagen and formed invasive structures in a three-dimensional culture assay. Ras related C3 botulinum toxin 1 (Rac1)-GTP levels were elevated in p190B transgenic tumors whereas Ras homologous A (RhoA) and cell division cycle 42 (Cdc42)-GTP levels were not significantly altered. Rac1 activity affects production of ROS, which regulate transformation, metastasis, and oxidative stress. Protein carbonylation, which is indicative of oxidative stress, was elevated 1.75-fold in p190B transgenic tumors as compared to control tumors suggesting that exogenous p190B expression may affect Rac1-dependent ROS production.Conclusions: These studies indicate that paradoxically, p190B RhoGAP, a major inhibitor of the Rho GTPases in vitro, has pro-tumorigenic functions that enhance MMTV-Neu induced mammary tumor formation and metastasis. Furthermore, exogenous p190B expression enhances cell adhesion and invasion, which may facilitate metastasis. Rac1 activity and oxidative stress are elevated in tumors expressing exogenous p190B suggesting that p190B may promote tumorigenesis through a Rac1/ROS dependent mechanism.

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