Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): Increased invasiveness may contribute to poor prognosis

Feng Ji Xu, Sharon Stack, Cinda Boyer, Kathy O'Briant, Regina Whitaker, Gordon Mills, Yin Hua Yu, Robert C. Bast

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage- independent growth while enhancing tyrosine phosphorylation of p185(c- erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.

Original languageEnglish (US)
Pages (from-to)1629-1634
Number of pages6
JournalClinical Cancer Research
Volume3
Issue number9
StatePublished - Sep 1 1997
Externally publishedYes

Fingerprint

Neuregulin-1
Breast Neoplasms
Antibodies
Matrix Metalloproteinase 9
Ovarian Neoplasms
Plastics
Tyrosine
Growth
Phosphorylation
Neoplasms
Membranes
Receptor Protein-Tyrosine Kinases
Intercellular Adhesion Molecule-1
Cell Adhesion
Anti-Idiotypic Antibodies
Ligands
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2) : Increased invasiveness may contribute to poor prognosis. / Xu, Feng Ji; Stack, Sharon; Boyer, Cinda; O'Briant, Kathy; Whitaker, Regina; Mills, Gordon; Yu, Yin Hua; Bast, Robert C.

In: Clinical Cancer Research, Vol. 3, No. 9, 01.09.1997, p. 1629-1634.

Research output: Contribution to journalArticle

@article{8372ed7b6ae34616a676ecc156b69a5f,
title = "Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): Increased invasiveness may contribute to poor prognosis",
abstract = "Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage- independent growth while enhancing tyrosine phosphorylation of p185(c- erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.",
author = "Xu, {Feng Ji} and Sharon Stack and Cinda Boyer and Kathy O'Briant and Regina Whitaker and Gordon Mills and Yu, {Yin Hua} and Bast, {Robert C.}",
year = "1997",
month = "9",
day = "1",
language = "English (US)",
volume = "3",
pages = "1629--1634",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2)

T2 - Increased invasiveness may contribute to poor prognosis

AU - Xu, Feng Ji

AU - Stack, Sharon

AU - Boyer, Cinda

AU - O'Briant, Kathy

AU - Whitaker, Regina

AU - Mills, Gordon

AU - Yu, Yin Hua

AU - Bast, Robert C.

PY - 1997/9/1

Y1 - 1997/9/1

N2 - Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage- independent growth while enhancing tyrosine phosphorylation of p185(c- erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.

AB - Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage- independent growth while enhancing tyrosine phosphorylation of p185(c- erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.

UR - http://www.scopus.com/inward/record.url?scp=0030879101&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030879101&partnerID=8YFLogxK

M3 - Article

C2 - 9815853

AN - SCOPUS:0030879101

VL - 3

SP - 1629

EP - 1634

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -