Necrosis and Hypoxia in Invasive Breast Carcinoma

Tomes, Ladislav; Emberley, Ethan; Niu, Yulian; Troup, Sandra; Pastorek, Jaromı́r; Strange, Karen; Harris, Adrian L.; Watson, Peter H.

doi:10.1023/a:1025476722493

Cited by 101 publications

(100 citation statements)

References 19 publications

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“…Hypoxia-inducible factor-1a is rapidly degraded within minutes of reoxygenation (Jiang et al, 1996), whereas CAIX has a half-life of 2 -3 days (Turner et al, 2002;Rafajova et al, 2004). This absence of an association is in agreement with reports (Tomes et al, 2003;Sobhanifar et al, 2005) of the presence of CAIX without HIF-1a expression in perinecrotic regions in solid tumours (Sobhanifar et al, 2005).…”

Section: Discussionsupporting

confidence: 85%

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

et al. 2009

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Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1a, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (Po0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (Po0.001). Fifty percent of basal-like tumours expressed HIF-1a, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (Po0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P ¼ 0.005), tumour grade (Po0.001) and oestrogen receptor (ER) negativity (Po0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (Po0.001 and P ¼ 0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.

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Section: Discussionsupporting

confidence: 85%

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

et al. 2009

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“…29 Further, this association was also observed in a study cohort of 153 stage I/II invasive breast cancers 26 but not in studies where only lymph node-positive patients were included. 27,28 In the present cohort, the correlation between NHG and HIF-1a expression persisted, also when analysing the lymph node-positive control cohort only (p 5 0.003).…”

Section: Discussionmentioning

confidence: 86%

“…14,19,20,26 In contrast, ER positivity has also been reported to be associated with HIF-1a expression, 18 whereas others have not observed any significant link between HIF-1a and ER expression. 27,28 Decreased ER expression and its downstream target PR in tumour cells surrounding necrotic zones are nevertheless obvious, 19,22,29 and despite some inconsistencies between studies, there seems to be an inverse link between HIF-1a expression and ER in both experimental models as well as in in vivo tumours. The data presented in this study further support a link between HIF-1a and the presence of ER in breast cancer but surprisingly not to the tamoxifen response, as further deliniated here.…”

Section: Discussionmentioning

confidence: 99%

“…HIF-1a has also been implicated as an independent prognostic marker in both lymph node-negative 26 as well as lymph node-positive breast cancers. 27,28 Also, high histological grade, ER and PR (progesterone receptor) negativity and the presence of necrotic regions have been linked to the presence of HIF-1a, 29 but the relation between histological grade, ER status and HIF-1a expression differs between reports. 14,26,27 This difference could potentially be explained by the fact that the role of HIF-1a as a prognostic marker was investigated in small cohorts of pre-and postmenopausal patients with both early and advanced breast cancer, receiving different forms of treatment.…”

mentioning

confidence: 99%

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Hypoxia inducible factor‐1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

Kronblad

Jirström

Rydén

et al. 2006

Intl Journal of Cancer

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Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor1a (HIF-1a), and HIF-1a has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1a regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1a using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1a was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1a expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1a protein expression was significantly associated with an impaired recurrence-free survival (p 5 0.014, 0.018). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1a expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1a might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis. ' 2005 Wiley-Liss, Inc.

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“…HIF-2a is associated with luminal breast cancer DP Stiehl et al were included as established histological markers of tissue hypoxia (Wykoff et al, 2000;Tomes et al, 2003). Rank order correlations confirmed that AREG and WISP2 were significantly more abundant in tumors also positive for HIF-2a, with correlation coefficients of 0.442 (Po0.01; n ¼ 192) and 0.264 (Po0.01; n ¼ 192), whereas PAI1 and CA9 showed no specific association with one particular HIF-a isoform, although both PAI1 and CA9 significantly correlated with HIF-a expression in general.…”

Section: Immunohistochemical Analyses Of Ca9 and Glut1mentioning

confidence: 99%

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible factors (HIFs) master the transcriptional response to local tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer patient survival in breast cancer with high levels of HIF-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-depleted cells was accompanied by reduced activation of epidermal growth factor (EGF) receptor family members. Apparently opposing results from patient and in vitro data point to an HIF-2a-dependent auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular models, increased the survival of diagnosed and treated human patients. Our findings suggest a model where HIF2a-mediated autocrine growth signaling in breast cancer sustains a state of cellular self-sufficiency, thereby masking unfavorable microenvironmental growth conditions, limiting adverse selection and improving therapy efficacy. Importantly, HIF-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Necrosis and Hypoxia in Invasive Breast Carcinoma

Cited by 101 publications

References 19 publications

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

Hypoxia inducible factor‐1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response

Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

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