EGFR activity in HER-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR.
Her-2/neu overexpression is an important prognostic parameter in breast cancer patients and has become a response predictor for trastuzumab treatment. Nevertheless, while trastuzumab is highly effective in many Her-2/neu overexpressing tumors, some do not respond. The reason for the differential effect is unknown, but it has been hypothesized that the complex interactions between Her-2/neu and other members of the EGFR family are involved in trastuzumab resistance. We have analyzed the protein expression of Her-2/neu, EGFR, and their activated forms, ptyr-1248 Her-2/neu, ptyr-845 EGFR and ptyr-1173 EGFR, in 57 Her-2/neu overexpressing breast tumors and investigated potential correlations between the receptors. By performing immunohistochemistry on paraffin-embedded tissue sections, we found that ptyr-845 EGFR was significantly co-expressed with Her-2/neu and ptyr-1248 Her-2/neu (p=0.043 and p=0.040, respectively), while ptyr-1173 EGFR was only correlated to Her-2/neu expression (p=0.042). Interestingly, EGFR and its activated forms were all significantly inversely correlated with PgR expression (p=0.011, p=0.033 and p=0.032, respectively), and ptyr-845 EGFR was also inversely correlated with ER expression (p=0.008). While we have previously shown that serum levels of the extracellular component of Her-2/neu are associated with tumoral ptyr-1248 Her-2/neu expression, we did not find a similar relationship between serum EGFR and intratumoral total/activated EGFR. We did, however, observe significantly higher levels of serum EGFR in women with 3+ overexpression of HER-2/neu (p=0.047). Taken together, we have demonstrated the activation pattern of EGFR and Her-2/neu in Her-2/neu overexpressing breast cancer. We suggest that EGFR inhibition might enhance the efficacy of trastuzumab by preventing cross-phosphorylation.
Gschwantler-Kaulich
Daphne
D
Division of Special Gynecology, Department of OB/GYN, Vienna Medical University, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Hudelist
Gernot
G
Koestler
Wolfgang J
WJ
Czerwenka
Klaus
K
Mueller
Ruth
R
Helmy
Samir
S
Ruecklinger
Ernst
E
Kubista
Ernst
E
Singer
Christian F
CF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases