BRCA1 tumours correlate with a HIF-1alpha phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression.
BACKGROUND
There are limited data regarding the hypoxia pathway in familial breast cancers. We therefore performed a study of hypoxic factors in BRCA1, BRCA2 and BRCAX breast cancers.


METHODS
Immunoperoxidase staining for HIF-1alpha, PHD1, PHD2, PHD3, VEGF and FIH was carried out in 125 (38 BRCA1, 33 BRCA2 and 54 BRCAX) breast carcinomas. These were correlated with clinicopathological parameters and the intrinsic breast cancer phenotypes.


RESULTS
BRCA1 tumours correlated with positivity for HIF-1alpha (P=0.008) and negativity for PHD3 (P=0.037). HIF-1alpha positivity (P=0.001), PHD3 negativity (P=0.037) and nuclear FIH negativity (P=0.011) was associated with basal phenotype. HIF-1alpha expression correlated with high tumour grade (P=0.009), negative oestrogen receptor (ER) status (P=0.001) and the absence of lymph node metastasis (P=0.028). Nuclear FIH expression and PHD3 correlated with positive ER expression (P=0.024 and P=0.035, respectively). BRCA1 cancers with positive HIF-1alpha or cytoplasmic FIH had a significantly shorter relapse-free survival (P=0.007 and P=0.049, respectively).


CONCLUSIONS
The aggressive nature of BRCA1 and basal-type tumours may be partly explained by an enhanced hypoxic drive and hypoxia driven ER degradation because of suppressed PHD and aberrantly located FIH expression. This may have important implications, as these tumours may respond to compounds directed against HIF-1alpha or its downstream targets.
Yan
M
M
Department of Pathology, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia.
Rayoo
M
M
Takano
E A
EA
Thorne
H
H
Fox
S B
SB
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D049308:Dioxygenases / Q000032:analysis / Q000502:physiology*; D050881:E1A-Associated p300 Protein / Q000502:physiology; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000032:analysis / Q000502:physiology*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis; D012097:Repressor Proteins / Q000502:physiology
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; D049308:Dioxygenases; C439790:HIF1AN protein, human; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human