Regulation of heparin-binding EGF-like growth factor expression in Ha-ras transformed human mammary epithelial cells.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA and protein expression is induced by EGF in MCF-10A nontransformed and Ha-ras transfected human mammary epithelial cells. The anti-EGF receptor (EGFR) blocking monoclonal antibody (MAb) 225 and the EGFR tyrosine kinase inhibitor PD153035 were able to inhibit the induction of HB-EGF mRNA levels in MCF-10A cells. However, the Ha-ras transformed MCF-10A cells were more refractory to inhibition by these agents and only a combination of the 225 MAb and PD153035 was able to significantly abrogate HB-EGF induction by EGF. The anti-erbB2 MAb L26 which interferes with heterodimer formation was able to block HB-EGF induction in response to EGF in MCF-10A cells and in the Ha-ras transformed cells only when used in combination with either the 225 MAb or PD153035. The MEK inhibitor PD90859 completely blocked EGF induction of HB-EGF mRNA levels in the nontransformed and Ha-ras transformed MCF-10A cells, which indicates that MAPK is involved in the signaling pathway of HB-EGF induction by EGF. An increase in the levels of HB-EGF may, therefore, be an important contributor to oncogenic transformation that is caused by Ha-ras overexpression in mammary epithelial cells. J. Cell. Physiol. 186:233-242, 2001. Published 2001 Wiley-Liss, Inc.
Martínez-Lacaci
I
I
Tumor Growth Factor Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
De Santis
M
M
Kannan
S
S
Bianco
C
C
Kim
N
N
Wallace-Jones
B
B
Wechselberger
C
C
Ebert
A D
AD
Salomon
D S
DS
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001940:Breast / Q000166:cytology*; D002448:Cell Adhesion; D002455:Cell Division; D002461:Cell Line, Transformed; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D006493:Heparin / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000276:immunology / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D000911:Antibodies, Monoclonal; D004815:Epidermal Growth Factor; D006493:Heparin; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C587883:HBEGF protein, human