Heregulin induces increase in sensitivity of an erbB-2-overexpressing breast cancer cell type to lysis by lymphokine-activated killer cells.
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 line 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.
Cardillo
M
M
Vincent T. Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
Yankelevich
B
B
Mazumder
A
A
Lupu
R
R
D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015979:Killer Cells, Lymphokine-Activated / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D016211:Transforming Growth Factor alpha; D014407:Tumor Cells, Cultured
D006023:Glycoproteins; D018799:Intercellular Adhesion Molecule-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; C092466:TGF-alpha-like 30-kDa glycoprotein, human