Abstract
BackgroundThe transcription factor hypoxia inducible factor (HIF) -1 drives tumor growth and metastasis and is associated with poor prognosis in breast cancer. Ascorbate can moderate HIF-1 activity in vitro and is associated with HIF pathway activation in a number of cancer types, but whether tissue ascorbate levels influence the HIF pathway in breast cancer is unknown. In this study we investigated the association between tumor ascorbate levels and HIF-1 activation and patient survival in human breast cancer.MethodsIn a retrospective analysis of human breast cancer tissue, we analysed primary tumor and adjacent uninvolved tissue from 52 women with invasive ductal carcinoma. We measured HIF-1α, HIF-1 gene targets CAIX, BNIP-3 and VEGF, and ascorbate content. Patient clinical outcomes were evaluated against these parameters.ResultsHIF-1 pathway proteins were upregulated in tumor tissue and increased HIF-1 activation was associated with higher tumor grade and stage, with increased vascular invasion and necrosis, and with decreased disease-free and disease-specific survival. Grade 1 tumors had higher ascorbate levels than did grade 2 or 3 tumors. Higher ascorbate levels were associated with less tumor necrosis, with lower HIF-1 pathway activity and with increased disease-free and disease-specific survival.ConclusionsOur findings indicate that there is a direct correlation between intracellular ascorbate levels, activation of the HIF-1 pathway and patient survival in breast cancer. This is consistent with the known capacity of ascorbate to stimulate the activity of the regulatory HIF hydroxylases and suggests that optimisation of tumor ascorbate could have clinical benefit via modulation of the hypoxic response.
Highlights
The transcription factor hypoxia inducible factor (HIF) -1 drives tumor growth and metastasis and is associated with poor prognosis in breast cancer
Anti- human HIF-1α, Carbonicanhydrase IX (CA-IX), Bcl-2/adenovirus E1B kDa interacting protein 3 (BNIP-3), and β-actin were from R&D Systems, Minneapolis, USA; anti-human Sodium-dependent vitamin C transporter - 2 (SVCT-2) was from Atlas Antibodies, Bromma, Sweden; anti-goat or anti-mouse HRP-conjugated antibodies were from DAKO, Australia
We monitored for effect of handling and storage, and noted that the HIF-1α protein content of both tumor and normal tissues did not vary over time (R2 = 0.0038 and 0.0152, respectively) which ranged from 2 to 14 years at -80 °C
Summary
The transcription factor hypoxia inducible factor (HIF) -1 drives tumor growth and metastasis and is associated with poor prognosis in breast cancer. Retrospective analysis of human tumor tissue samples has revealed that increased ascorbate levels were associated with reduced HIF-1 pathway activity in endometrial [27], colorectal [26], papillary renal cell carcinoma [33] and thyroid tumor tissue [34], and with improved disease-free survival in colorectal cancer patients [26]. This data suggests that increased ascorbate availability dampens the tumor HIF-1 response and may mitigate the effects of tumor hypoxia. Whether a similar relationship exists in breast cancer is unknown
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