Abstract
PurposeInhibition of hypoxia-inducible factor (HIF) and Axl receptor tyrosine kinase is being evaluated for targeted therapy in solid tumors. Both HIF-1α and Axl influence tumor growth and metastatic potential, and they have been linked to treatment failure in many cancers. However, there is a lack of reports on HIF-1α expression in African breast cancer, which has a poor prognosis, and novel treatment targets must therefore be established. Here, we aimed to evaluate HIF-1α in relation to Axl expression, angiogenesis markers, and other tumor characteristics in a series of African breast cancer.MethodsUsing immunohistochemistry, we examined 261 invasive breast cancers on tissue microarrays for HIF-1α and Axl as well as several other markers, and a subset of 185 cases had information on VEGF (vascular endothelial growth factor) expression, microvessel density (MVD), proliferating microvessel density (pMVD) and vascular proliferation index (VPI) for important comparisons.ResultsStrong HIF-1α expression was associated with increased Axl (p = 0.007), VEGF (p<0.0005), and p53 (p = 0.032) expression, as well as high tumor cell proliferation by Ki-67 (p = 0.006), and high tumor grade (p = 0.003). Tumors with strong HIF-1α expression had significantly higher MVD (p = 0.019) and higher pMVD (p = 0.027) than tumors with weak expression.ConclusionsHigh HIF-1α expression is significantly associated with Axl and VEGF expression, and with markers of poor prognosis in this series of breast cancer, suggesting HIF-1α and Axl as potential therapeutic targets in African breast cancer.
Highlights
Breast cancer is the most common malignancy affecting females worldwide, and it caused about 500,000 deaths in 2012, which is about 15% of all cancer deaths in women [1]
We examined 261 invasive breast cancers on tissue microarrays for hypoxia-inducible factor (HIF)-1α and Axl as well as several other markers, and a subset of 185 cases had information on vascular endothelial growth factor (VEGF) expression, microvessel density (MVD), proliferating microvessel density and vascular proliferation index (VPI) for important comparisons
Strong HIF-1α expression was associated with increased Axl (p = 0.007), VEGF (p
Summary
Breast cancer is the most common malignancy affecting females worldwide, and it caused about 500,000 deaths in 2012, which is about 15% of all cancer deaths in women [1]. Regarding breast cancer in Africans and African Americans, previous studies have revealed that it has more aggressive features, is usually diagnosed in later stages, and has a poorer prognosis than breast cancer among Caucasians [3,4,5]. The reasons for this have not been fully characterized [4]. HIF-1 is a main regulator of vascular endothelial growth factor (VEGF) and modulates angiogenesis by up-regulating the VEGF gene [6, 9, 10]. Sustained angiogenesis is one of the hallmarks of cancer [12] and is a complex multi-step process, being essential for tumor growth, invasion and metastatic spread [6, 11, 13]
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