ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis.
BACKGROUND
The aim of this study is to provide an expression profile of ErbB/HER ligands in breast cancer. We analysed the relationships with their receptors, the bio-pathological features and prognosis.


METHODS
Epidermal growth factor (EGF), transforming growth factor-alpha (TGFalpha), amphiregulin (AREG), betacellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), epiregulin (EREG) and neuregulins1-4 (NRG1-4) were quantified in 363 tumours by real-time reverse transcription-polymerase chain reaction using TaqMan probes.


RESULTS
Ligands were detected in 80%-96% of the cases, except NRG3 (42%) and EREG (45.5%). At least one ligand was expressed in 304 cases (cut-off: upper quartile). Almost all combinations of receptor and ligand co-expressions were observed, but TGFalpha is preferentially expressed in tumours co-expressing EGFR/HER3, NRG3 in those co-expressing EGFR/HER4, AREG and EREG in those co-expressing HER2/HER4. EGF and AREG were associated with estradiol receptors, small tumour size, low histoprognostic grading, high HER4 levels. TGFalpha, HB-EGF and NRG2 were negatively related to these parameters. In Cox univariate analyses, EGF was a prognostic factor.


CONCLUSIONS
Our study demonstrates that (i) ErbB/HER ligands, including BTC and EREG, are expressed in most breast cancers; and (ii) TGFalpha, HB-EGF and NRG2 high expressions are related to the biological aggressiveness of the tumours.
Révillion
F
F
Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, BP 307, 59020 Lille Cedex, France. f-revillion@o-lambret.fr
Lhotellier
V
V
Hornez
L
L
Bonneterre
J
J
Peyrat
J-P
JP
D066258:Amphiregulin; D066259:Betacellulin; D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D018275:Carcinoma, Lobular / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000032:analysis; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000032:analysis; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis* / Q000235:genetics; D009414:Nerve Growth Factors / Q000032:analysis; D009419:Nerve Tissue Proteins / Q000032:analysis; D020890:Neuregulin-1; D020880:Neuregulins / Q000032:analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000032:analysis; D016211:Transforming Growth Factor alpha / Q000032:analysis
D066258:Amphiregulin; D066259:Betacellulin; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D066260:Epiregulin; D066246:ErbB Receptors; D006023:Glycoproteins; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D020880:Neuregulins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D016211:Transforming Growth Factor alpha; C587848:AREG protein, human; C587851:BTC protein, human; C587880:EREG protein, human; C587883:HBEGF protein, human; C094131:NRG1 protein, human; C106766:NRG2 protein, human; C486357:NRG3 protein, human; C467747:neuregulin-4; C512478:EGFR protein, human