Expression of hypoxia-inducible factor (HIF-1alpha), VEGF-C and VEGF-D in non-invasive and invasive breast ductal carcinomas.
BACKGROUND
Hypoxia-inducible factor 1 alpha (HIF-1alpha) is a transcription factor that may play an important role in tumour growth and metastasis by its regulation of angiogenesis and lymphangiogenesis to survive cellular hypoxia. Lymphangiogenesis is promoted by vascular endothelial growth factors (VEGF)-C and VEGF-D, but the correlation between the expression of HIF-1alpha and VEGF-C or VEGF-D in human breast carcinoma is not well elucidated. This study examined the pathobiological role of these molecules in human breast ductal carcinoma.


METHODS
The expressions of HIF-1alpha, VEGF-C and VEGF-D were analyzed in 10 normal mammary epithelia, 12 fibroadenomas, 20 ductal carcinomas in situ (DCISs and 36 invasive ductal carcinomas (IDCs) by immunohistochemistry, comparing clinicopathological parameters.


RESULTS
HIF-1alpha expression in nuclei was found in DCIS and IDC, but not in normal or fibroadenoma cells. The HIF-1alpha labelling index was significantly correlated with the degree of VEGF-C expression in IDC (p < 0.001), but not in DCIS. HIF-1alpha expression was significantly correlated with tumour necrosis and with the Van Nuys prognostic index (VNPI) (p < 0.05, p < 0.05, respectively) in the 20 DCISs. On the other hand, VEGF-D levels, but not those of HIF-1alpha and VEGF-C, were significantly higher in cases with lymph node metastasis and estrogen receptor expression in carcinoma cells (p < 0.01, p < 0.05, respectively) in the 36 IDCs.


CONCLUSIONS
These findings suggest that HIF-1alpha is expressed in the early stage of mammary carcinogenesis, in which the expression correlates with necrosis in the DCISs and with VEGF-C expression in the IDCs, the latter resulting in a higher frequency of metastasis to regional lymph nodes.
Okada
Koichiro
K
Division of Organ Regeneration Surgery, Department of Surgery, Faculty of Medicine, Tottori University, 86 Nishi-cho Yonago, Tottori 683-8503, Japan.
Osaki
Mitsuhiko
M
Araki
Kunio
K
Ishiguro
Kiyosuke
K
Ito
Hisao
H
Ohgi
Shigetsugu
S
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D044584:Carcinoma, Ductal / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018226:Fibroadenoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D014157:Transcription Factors / Q000096:biosynthesis*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D