HER2/neu expression correlates with vascular endothelial growth factor-C and lymphangiogenesis in lymph node-positive breast cancer.
BACKGROUND
Vascular endothelial growth factor-C (VEGF-C) is the main inducer of lymphangiogenesis. VEGF-C overexpression is associated with lymphovascular tumor cell invasion, an increased rate of lymph node metastasis and adverse prognosis in various human cancers. However, little is known about the upstream inducers of VEGF-C expression. Recent studies have shown that human epidermal growth factor receptor 2 (HER2/neu) overexpression is associated with high VEGF-C levels in human breast cancer cells. In addition to blocking of HER2/neu, tyrosine kinase significantly decreased VEGF-C expression in vitro.


METHODS
VEGF-C expression, lymphatic microvessel density (LMVD), lymphovascular invasion (LVI) and HER2/neu expression were evaluated with immunohistochemical/FISH methods in a collective of 150 lymph node-positive human breast cancers with long-term follow-up.


RESULTS
Cases with 3+ HER2/neu protein expression showed a significantly stronger VEGF-C expression than all others cases (P = 0.006). In addition, we found a significant correlation between VEGF-C expression and LMVD (P = 0.012) and a strong positive association between LMVD and LVI (P < 0.001).


CONCLUSIONS
Our data provide evidence for a clinically relevant association between HER2/neu and VEGF-C expression in human breast cancer. Inhibiting HER2/neu may reduce tumor progression by blocking VEGF-C-mediated tumor cell proliferation and lymphogenic metastasis.
Schoppmann
S F
SF
Department of Surgery, Medical University of Vienna, Vienna, Austria. sebastian.schoppmann@meduniwien.ac.at
Tamandl
D
D
Roberts
L
L
Jomrich
G
G
Schoppmann
A
A
Zwrtek
R
R
Dubsky
P
P
Gnant
M
M
Jakesz
R
R
Birner
P
P
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D018275:Carcinoma, Lobular / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D042582:Vascular Endothelial Growth Factor C; C467486:VEGFC protein, human; C508053:ERBB2 protein, human