Plasma levels of HER-2/neu, tumor type M2 pyruvate kinase and its tyrosine-phosphorylated metabolite in advanced breast cancer.
BACKGROUND
Tyrosine kinase signal transduction pathways are a focus of interest for therapeutic interventions. The oncoprotein HER-2/neu shows tyrosine kinase activity leading to phosphorylation and activation of numerous second-messenger systems. One target of phosphorylation processes is assumed to be the tumor type M2 isoenzyme of pyruvate kinase (TuM2-PK) which has been shown to be elevated in metastatic breast cancer.


METHODS
We measured the plasma levels of HER-2/neu, TuM2-PK and tyrosine-phosphorylated TuM2-PK (p-TuM2-PK) in 69 patients (pts) with breast cancer and correlated these parameters to each other and to the classical tumor marker CA 27.29. The samples were measured with ELISA assays while CA 27.29 was determined with an automated chemiluminescence assay. For analysis, we formed 5 subgroups according to the plasma HER-2/neu levels (group 1: < 15 ng/ml, n = 28; group 2: 15 < or = x < 50 ng/ml, n = 21; group 3: 50 < or = x < 100 ng/ml, n = 9; group 4: 100 < or = x < 500 ng/ml, n = 7; group 5: > or = 500 ng/ml, n = 4).


RESULTS
From the HER-2/neu group 1 to group 5, there was a statistically significant increase of CA 27.29 from 35.8 U/ml to 1095.8 U/ml (p < 0.001). There was also a trend for increasing TuM2-PK levels with increasing HER-2/neu levels (p = 0.126). From the lowest extinction (0.088) to the highest extinction result (2.167) of p-TuM2-PK we found a 25-fold increase, which was reproducible in spiking and dilution experiments proving that TuM2-PK is phosphorylated at tyrosine residues to a certain extent. However, there was no correlation between plasma HER-2/neu and p-TuM2-PK levels.


CONCLUSIONS
TuM2-PK is phosphorylated at tyrosine residues in breast cancer patients. Using the shed antigen of HER-2/neu in plasma as a surrogate marker, we did not find any evidence that this phosphorylation is initiated by the oncoprotein HER-2/neu.
Lüftner
D
D
Medizinische Klinik und Poliklinik II, Universitätsklinikum Charité, Campus Mitte, Humboldt-Universität zu Berlin, Schumannstr. 20-21, 10117 Berlin, Germany. Diana.Lueftner@rz.hu-berlin.de
Mazurek
S
S
Henschke
P
P
Mesterharm
J
J
Schildhauer
S
S
Geppert
R
R
Wernecke
K D
KD
Possinger
K
K
D000328:Adult; D000368:Aged; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000473:pathology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000097:blood; D008875:Middle Aged; D009367:Neoplasm Staging; D019000:Phosphotyrosine / Q000097:blood*; D011505:Protein-Tyrosine Kinases / Q000097:blood; D011770:Pyruvate Kinase / Q000097:blood*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis
D015295:Antigens, Tumor-Associated, Carbohydrate; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D011770:Pyruvate Kinase; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C090797:CA 27-29 antigen