p300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer

In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)–1a in breast cancer, especially the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition for transcriptional coactivators such as p300. The aim of this study was therefore to explore the role of p53 and p300 in relation to overexpression of HIF-1a and activation of HIF-1 downstream genes in invasive breast cancer. p300 immunohistochemistry was performed in a group of 183 early-stage invasive breast cancers, and related to p53 accumulation, overexpression of HIF-1a, and several HIF-1 downstream genes. p300 was expressed in varying degrees in 84% of invasive breast cancers. p300 staining intensity correlated positively with HIF-1a expression ( P = .04), p53 accumulation ( P = .001), and overexpression of glucose transporter 1 (GLUT-1) ( P b .001), a glucose transporter downstream target gene of HIF-1. GLUT-1 levels were significantly associated with p300 in HIF-1a positive patients ( P = .02). p53 accumulation significantly positively correlated with carbonic anhydrase IX (CAIX)/GLUT-1 coexpression in HIF-1a–positive patients ( P = .007). p53 accumulation/high p300 levels, the most favorable situation for HIF-1 downstream activation, were significantly associated with GLUT-1 overexpression ( P = .01) and coexpression of CAIX/GLUT-1 ( P = .03), compared with low p53/low p300 levels, the most unfavorable situation for HIF-1 downstream activation. p300 is a cofactor highly associated with p53 accumulation and HIF-1a levels in invasive breast cancer. Furthermore, low levels of p300 may explain absence of downstream effects in HIF-1a–overexpressing cancers, an effect that seems to be enhanced by wild-type levels of p53. This underlines the importance of p300 levels and p53 accumulation in the HIF-1–regulated response toward hypoxia

Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer

Background: Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1a concentrations increase during breast carcinogenesis, and are associated with poor prognosis. An earlier study noted two HIF-1a overexpression patterns: diffuse scattered throughout the tissue and confined to perinecrotic cells. Aims: To investigate the prognostic impact of these different HIF-1a overexpression patterns in relation to its downstream effectors carbonic anhydrase (CA) IX and glucose transporter 1 (GLUT-1). Methods: HIF-1a, CA IX, and GLUT-1 expression was studied by immunohistochemistry, including double staining for CA IX and HIF-1a. Clinical data included disease free survival, lymph node status, and tumour size. Results: HIF-1a overexpression (44% of cases) had a perinecrotic (13.5%) or diffuse staining pattern (30.5%). CA IX expression was detectable in 12.5% of breast cancers, whereas GLUT-1 expression was seen in 29%, with both showing perinecrotic membrane staining. Perinecrotic HIF-1a overexpression was highly associated with CA IX and GLUT-1 overexpression, and double staining for HIF-1a and CA IX showed strong expression in the same cells. Diffusely overexpressed HIF-1a was not associated with CA IX or GLUT-1 expression. Patients with diffuse HIF-1a staining had a significantly better prognosis than patients with perinecrotically overexpressed HIF-1a. Conclusions: Different regulation pathways of HIF-1a overexpression exist in breast cancer: (1) hypoxia induced, perinecrotic HIF-1a overexpression with strong expression of hypoxia associated genes (CA IX and GLUT-1), which is associated with a poor prognosis; and (2) diffuse HIF-1a overexpression lacking major hypoxia associated downstream effects, resulting in a more favourable prognosis