Background The 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. Methods In 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. Results HIF-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. Conclusions Our 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.

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BackgroundNew Zealand Māori have a poorer outcome from breast cancer than non-Māori, yet prognostic data are sparse. The objective of this study was to quantify levels of prognostic factors in a cohort of self-declared Māori and European breast cancer patients from Christchurch, New Zealand.Methods and ResultsClinicopathological and survival data from 337 consecutive breast cancer patients (27 Māori, 310 European) were evaluated. Fewer tumours were high grade in Māori women than European women (p = 0.027). No significant ethnic differences were detected for node status, tumour type, tumour size, human epidermal growth factor receptor, oestrogen and progesterone receptor (ER/PR) status, or survival.In addition, tumour and serum samples from a sub-cohort of 14 Māori matched to 14 NZ European patients were analyzed by immunohistochemistry and enzyme linked immunosorbent assay for molecular prognostic factors. Significant correlations were detected between increased grade and increased levels of hypoxia inducible factor-1 (HIF-1α), glucose transporter-1 (GLUT-1), microvessel density (MVD) and cytokeratins CK5/6 (p < 0.05). High nodal status correlated with reduced carbonic anhydrase IX (CA-IX). Negative ER/PR status correlated with increased GLUT-1, CA-IX and MVD. Within the molecular factors, increased HIF-1α correlated with raised GLUT-1, MVD and CK5/6, and CK5/6 with GLUT-1 and MVD (p < 0.05). The small number of patients in this sub-cohort limited discrimination of ethnic differences.ConclusionsIn this Christchurch cohort of breast cancer patients, Māori women were no more likely than European women to have pathological or molecular factors predictive of poor prognosis. These data contrast with data from the North Island NZ, and suggest potential regional differences.

Introduction:We aimed to investigate the impact of radiation treatment in early-stage triple negative breast cancer (TNBC). Methods: Patients with early stage (T1-3, N0-2, M0) TNBC were identified using the New Zealand breast cancer register. The outcomes of local recurrence (LRFR), local recurrence free survival (LRFS), loco-regional recurrence free rate (LRRFR), loco-regional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), metastasis free (MFS) and overall survival (OS) were determined. Predefined univariate and multivariate cox regression analyses were used to explore associations between known prognostic and treatment factors. Results: 1209 patients were identified with a median follow-up of 3.88 years. The majority were post-menopausal. The mean tumour size was 26mm, the majority had grade III disease and a third were node positive. 625 patients had mastectomy and 584 had breast conservation surgery (BCS). 92% of BCS and 38% of mastectomy patients received radiation. 67% received adjuvant chemotherapy. The 5 year OS was 77.6% (95% CI 74.6-80.2), 5 year BSS was 82.1% (95%CI 79.1-84.7), 5 year LRRFS was 73.9% (95% CI 73.87-73.93), 5 year LRFS was 75.4 (75.37-75.43) and the 5 year LRFR was 92.4% (95% CI 90.6-94.2). The significant prognostic/predictive factors for OS were adjuvant radiation treatment, chemotherapy, T stage, lymph node involvement and lympho-vascular space invasion. Results were similar for BSS, DMFS, LRFS and LRRFS except that LVSI was not significantly associated with BCSS, LRFS or LRRFS. When analysed by surgical type, in the WLE group, radiation was found to be significantly associated with improvement in all outcomes. In mastectomy group, radiation was not found to be significant for BCSS, LRFS, LRRFS or OS. Conclusion: Radiation treatment is significantly associated with improved outcomes in early stage TNBC. This argues against the hypothesis that TNBC has inherent radiation resistance.