Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells

Lydia Puricelli, Cecilia J. Proiettii, Leticia Labriola, Mariana Salatino, María E. Balañá, Julio Aguirre Ghiso, Ruth Lupu, Omar P. Pignataro, Eduardo H. Charreau, E. B K De Joffé, Patricia V. Elizalde

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGβ1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGβ1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGβ1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGβ1 action indicated that the addition of HRGβ1 to LM3 cells resulted in activation of phosphatidylinositol 3-kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGβ1 also caused the rapid activation of ERKI/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGβ1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEKI/ERKs activity with PD98059, resulted in suppression of the ability of HRGβ1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGβ1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGβ1-induced proliferation appear to be distinct from those involved in HRGβ1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.

Original languageEnglish (US)
Pages (from-to)642-653
Number of pages12
JournalInternational Journal of Cancer
Volume100
Issue number6
DOIs
StatePublished - Aug 20 2002
Externally publishedYes

Fingerprint

Neuregulin-1
Plasminogen Activators
Urokinase-Type Plasminogen Activator
Phosphatidylinositols
Phosphatidylinositol 3-Kinase
Phosphotransferases
Breast Neoplasms
Neoplasm Metastasis
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Receptor Protein-Tyrosine Kinases
Transducers
Cell Movement
Tyrosine
Peptide Hydrolases
Phosphorylation
Cell Line
Enzymes
Growth

Keywords

  • ErbB receptors
  • ERKs
  • Heregulin
  • Metastatic mammary tumors
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. / Puricelli, Lydia; Proiettii, Cecilia J.; Labriola, Leticia; Salatino, Mariana; Balañá, María E.; Ghiso, Julio Aguirre; Lupu, Ruth; Pignataro, Omar P.; Charreau, Eduardo H.; De Joffé, E. B K; Elizalde, Patricia V.

In: International Journal of Cancer, Vol. 100, No. 6, 20.08.2002, p. 642-653.

Research output: Contribution to journalArticle

Puricelli, Lydia ; Proiettii, Cecilia J. ; Labriola, Leticia ; Salatino, Mariana ; Balañá, María E. ; Ghiso, Julio Aguirre ; Lupu, Ruth ; Pignataro, Omar P. ; Charreau, Eduardo H. ; De Joffé, E. B K ; Elizalde, Patricia V. / Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. In: International Journal of Cancer. 2002 ; Vol. 100, No. 6. pp. 642-653.
@article{baa0451205dc483f8d7bc120d440f1b7,
title = "Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells",
abstract = "Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGβ1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGβ1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGβ1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGβ1 action indicated that the addition of HRGβ1 to LM3 cells resulted in activation of phosphatidylinositol 3-kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGβ1 also caused the rapid activation of ERKI/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGβ1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEKI/ERKs activity with PD98059, resulted in suppression of the ability of HRGβ1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGβ1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGβ1-induced proliferation appear to be distinct from those involved in HRGβ1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.",
keywords = "ErbB receptors, ERKs, Heregulin, Metastatic mammary tumors, Phosphatidylinositol 3-kinase",
author = "Lydia Puricelli and Proiettii, {Cecilia J.} and Leticia Labriola and Mariana Salatino and Bala{\~n}{\'a}, {Mar{\'i}a E.} and Ghiso, {Julio Aguirre} and Ruth Lupu and Pignataro, {Omar P.} and Charreau, {Eduardo H.} and {De Joff{\'e}}, {E. B K} and Elizalde, {Patricia V.}",
year = "2002",
month = "8",
day = "20",
doi = "10.1002/ijc.10533",
language = "English (US)",
volume = "100",
pages = "642--653",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells

AU - Puricelli, Lydia

AU - Proiettii, Cecilia J.

AU - Labriola, Leticia

AU - Salatino, Mariana

AU - Balañá, María E.

AU - Ghiso, Julio Aguirre

AU - Lupu, Ruth

AU - Pignataro, Omar P.

AU - Charreau, Eduardo H.

AU - De Joffé, E. B K

AU - Elizalde, Patricia V.

PY - 2002/8/20

Y1 - 2002/8/20

N2 - Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGβ1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGβ1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGβ1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGβ1 action indicated that the addition of HRGβ1 to LM3 cells resulted in activation of phosphatidylinositol 3-kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGβ1 also caused the rapid activation of ERKI/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGβ1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEKI/ERKs activity with PD98059, resulted in suppression of the ability of HRGβ1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGβ1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGβ1-induced proliferation appear to be distinct from those involved in HRGβ1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.

AB - Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGβ1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGβ1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGβ1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGβ1 action indicated that the addition of HRGβ1 to LM3 cells resulted in activation of phosphatidylinositol 3-kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGβ1 also caused the rapid activation of ERKI/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGβ1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEKI/ERKs activity with PD98059, resulted in suppression of the ability of HRGβ1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGβ1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGβ1-induced proliferation appear to be distinct from those involved in HRGβ1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.

KW - ErbB receptors

KW - ERKs

KW - Heregulin

KW - Metastatic mammary tumors

KW - Phosphatidylinositol 3-kinase

UR - http://www.scopus.com/inward/record.url?scp=0037143784&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037143784&partnerID=8YFLogxK

U2 - 10.1002/ijc.10533

DO - 10.1002/ijc.10533

M3 - Article

C2 - 12209601

AN - SCOPUS:0037143784

VL - 100

SP - 642

EP - 653

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 6

ER -