Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy

Introduction Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1 alpha is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1 alpha as aTNBC-specific marker. Methods 62 TNBC, 64 HER2(+), and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1 alpha, HIF-1 beta, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR) evaluation of HIF-1 alpha and VEGF transcripts was performed on 54 cases (18 from each subtype). Results HIF-1 alpha protein was expressed in 35.5% TNBC, 45.3% HER2(+) and 25.0% ER+/PR+ (p = 0.055; chi(2) test). PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1 alpha protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1 alpha protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; chi(2) test), while MVD was comparable among all groups (p = 0.928; chi(2) test). VEGFR3 was highest in TNBC expressing HIF-1 alpha. HIF-1 beta protein was expressed in 32.0% of HIF-1 alpha(+), and in (44.3%) of HIF-1 alpha(-) breast cancer cases (p = 0.033; chi(2) test). Moreover, HIF-1 alpha expression in cases with central fibrosis and necrosis was highest in the HER2(+) followed by the TNBC (p = 0.156; chi(2)test). Conclusions A proportion of TNBC express HIF-1 alpha but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1 alpha targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the setting of clinically aggressive or refractory disease.