Heregulin induces increase in sensitivity of an erbB-2-overexpressing breast cancer cell type to lysis by lymphokine-activated killer cells

Marina Cardillo, Boris Yankelevich, Amithaba Mazumder, Ruth Lupu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The erbB-2 oncoprotein is overexpressed in 30% of tumors from breast and ovarian cancer patients and it is related to poor overall and disease-free survival. In vitro studies on erbB-2-overexpressing cells have found a strong correlation between this oncogene overexpression and relative resistance to lymphokine-activated killer (LAK) cell lysis. gp30/heregulin/NDF (neu differentiation factor), indirect activators of erbB-2, are able to induce a more differentiated phenotype on erbB-2-overexpressing, erbB-3- and/or erbB-4-positive breast cancer cells. We tested the ability of these highly homologous growth factors to stimulate LAK cell lysis of breast cancer cells. Our experiments demonstrated a marked increase in LAK cell cytotoxicity towards an erbB-2-overexpressing, erbB-3-positive cell link by treatment of these cells with heregulin for 72 h. In contrast we did not observe any enhancement of lysis of MCF-7, a cell line that does not overexpress erbB-2 and is positive for the erbB-3 and erbB-4 receptors, after treatment with heregulin. The increased lysis was associated with upregulation of intercellular adhesion molecule 1 (ICAM-1), down-regulation of erbB-2 and increased binding between breast cancer cells and LAK cells. Pre incubation of target (SKBR3) cells with blocking anti-ICAM-1 antibody completely abrogated the enhanced cytotoxicity. A similar effect was observed by pretreatment of the effector (LAK) cells with antibodies directed against LFA-1, the receptor for ICAM-1. These results suggest the possible utilization of gp30/heregulin in the treatment of breast cancer patients by its ability to stimulate patient immune responses.

Original languageEnglish (US)
Pages (from-to)19-25
Number of pages7
JournalCancer Immunology Immunotherapy
Volume43
Issue number1
DOIs
StatePublished - 1996
Externally publishedYes

Fingerprint

Neuregulin-1
Lymphokine-Activated Killer Cells
Breast Neoplasms
Intercellular Adhesion Molecule-1
Lymphocyte Function-Associated Antigen-1
Antibodies
Oncogene Proteins
MCF-7 Cells
Oncogenes
Ovarian Neoplasms
Disease-Free Survival
Intercellular Signaling Peptides and Proteins
Up-Regulation
Therapeutics
Down-Regulation
Phenotype
Cell Line

Keywords

  • erbB-2
  • erbB-3
  • erbB-4
  • Heregulin
  • LAK

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

Cite this

Heregulin induces increase in sensitivity of an erbB-2-overexpressing breast cancer cell type to lysis by lymphokine-activated killer cells. / Cardillo, Marina; Yankelevich, Boris; Mazumder, Amithaba; Lupu, Ruth.

In: Cancer Immunology Immunotherapy, Vol. 43, No. 1, 1996, p. 19-25.

Research output: Contribution to journalArticle

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abstract = "The erbB-2 oncoprotein is overexpressed in 30{\%} of tumors from breast and ovarian cancer patients and it is related to poor overall and disease-free survival. In vitro studies on erbB-2-overexpressing cells have found a strong correlation between this oncogene overexpression and relative resistance to lymphokine-activated killer (LAK) cell lysis. gp30/heregulin/NDF (neu differentiation factor), indirect activators of erbB-2, are able to induce a more differentiated phenotype on erbB-2-overexpressing, erbB-3- and/or erbB-4-positive breast cancer cells. We tested the ability of these highly homologous growth factors to stimulate LAK cell lysis of breast cancer cells. Our experiments demonstrated a marked increase in LAK cell cytotoxicity towards an erbB-2-overexpressing, erbB-3-positive cell link by treatment of these cells with heregulin for 72 h. In contrast we did not observe any enhancement of lysis of MCF-7, a cell line that does not overexpress erbB-2 and is positive for the erbB-3 and erbB-4 receptors, after treatment with heregulin. The increased lysis was associated with upregulation of intercellular adhesion molecule 1 (ICAM-1), down-regulation of erbB-2 and increased binding between breast cancer cells and LAK cells. Pre incubation of target (SKBR3) cells with blocking anti-ICAM-1 antibody completely abrogated the enhanced cytotoxicity. A similar effect was observed by pretreatment of the effector (LAK) cells with antibodies directed against LFA-1, the receptor for ICAM-1. These results suggest the possible utilization of gp30/heregulin in the treatment of breast cancer patients by its ability to stimulate patient immune responses.",
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