Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

Span, Paul N.; Bussink, Johan; Manders, Peggy; Beex, L.V.A.M.; Sweep, Fred C.G.J.

doi:10.1038/sj.bjc.6601122

Cited by 103 publications

(86 citation statements)

References 25 publications

(25 reference statements)

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“…This is in keeping with our studies in the neoadjuvant context, in which CAIX was associated with a shorter relapse-free survival in patients treated with CMF (Generali et al, 2006a, b), and in patients treated in the adjuvant setting, in which CAIX measured by RT -PCR was associated with chemoresistance (Span et al, 2003). Thus, these data suggest that CAIX is predictive rather than prognostic.…”

Section: Discussionsupporting

confidence: 72%

“…In this series, those patients with tumours of either a basallike phenotype or expressing CAIX were associated with an adverse outcome. Nevertheless, in this study and in others reported earlier, CAIX expression is also positively correlated with high tumour grade and size (Chia et al, 2001;Span et al, 2003), the former feature also characteristic of basal tumours. Thus, hypoxic stress may not be part of the basal intrinsic subtype but might be due to an association with grade.…”

Section: Discussioncontrasting

confidence: 39%

“…Carbonic anhydrase IX is a transmembrane protein involved in maintaining a low pericellular pH through its reversible conversion of carbon dioxide and water into carbonic acid (Pastorek et al, 1994;Opavsky et al, 1996), and has been shown to maintain survival of breast tumour cells under hypoxic conditions (Potter and Harris, 2003). Carbonic anhydrase IX is not present in normal breast tissues (Bartosova et al, 2002), but is upregulated in invasive tumours with increasing intensity, with increasing distance from tumour vessels (Span et al, 2003) tightly under the regulation of HIF-1a (Grabmaier et al, 2004). Carbonic anhydrase IX expression has been shown to correlate with the distribution of pimonidazole, a chemical marker of hypoxia (Opavsky et al, 1996;Wykoff et al, 2000) and with hypoxia measured by Eppendorf microelectrode in advanced cervical cancer (Loncaster et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

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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: 72%

Section: Discussioncontrasting

confidence: 39%

Section: Discussionmentioning

confidence: 99%

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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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“…30 In addition, CA9 transcription, detected by either semiquantitative or quantitative RT-PCR, has been associated with malignant breast tissues and treatment outcome. 18,37 Therefore, CA9 was chosen as a cancer-related marker for our study. We confirmed its expression in primary vulvar carcinomas by both immunohistochemistry and nested RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

Detection of carbonic anhydrase 9–expressing tumor cells in the lymph nodes of vulvar carcinoma patients by RT‐PCR

Kowalewska

Radziszewski

Kulik

et al. 2005

Intl Journal of Cancer

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Regional lymph node status is an important prognostic factor for vulvar cancer. The goal of our study was to elaborate a reliable test for detecting micrometastases, undetectable by traditional methods, in the lymph nodes of vulvar squamous carcinoma patients. For this purpose, carbonic anhydrase-9 (CA9) was investigated as a cancer-related marker by RT-PCR. Firstly, primary carcinoma specimens were examined for CA9 expression by immunohistochemistry with M75 monoclonal antibody. All 19 tissues exhibited a variable degree of staining, which was mostly confined to the plasma membranes of tumor cells. Correspondingly, all primary tumor specimens and the control A-431 vulvar cancer cell line gave a positive signal in the nested RT-PCR assay designed to detect CA9-expressing cells with a high sensitivity. Analysis of 77 lymph node specimens from 20 patients revealed a full correlation between RT-PCR results and standard hematoxylin-eosin staining in 75% of samples, whereas 25% of specimens were negative by the standard method and positive for CA9 mRNA, accounting for 28% of all histologically negative lymph nodes. There were no false-negatives with RT-PCR. A positive inguinal lymph node with a negative sentinel node was observed in the same groin only once in 38 specimens. Our findings clearly indicate potential value of CA9 as a molecular marker for the assessment of regional lymph node status in vulvar cancer patients and support a possible utility of our RT-PCR assay in the detection of micrometastases. ' 2005 Wiley-Liss, Inc.

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“…[13][14][15][16][17][18][19][20][21][22][23][24] Furthermore, only one study evaluated the response of tamoxifen according to HIF-1 expression and an independent report analyzed the predictive value of CA IX measured by RT-PCR. 21,24 However, no study addressed the impact on survival and treatment outcome of both together, HIF-1a and CA IX, in breast cancer. Because of the controversial results and also because we speculated that combination of HIF-1a and CA IX, one of its downstream target, might provide additional information, we performed the present study.…”

mentioning

confidence: 99%

HIF‐1α and CA IX staining in invasive breast carcinomas: Prognosis and treatment outcome

Trastour¹,

Benizri²,

Ettore³

et al. 2007

Intl Journal of Cancer

208

154

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Hypoxia stabilizes HIF-1a (Hypoxia Inducible Factor-1a), which then triggers the expression of several genes involved in many aspects of cancer progression, including metabolic adaptation, cell survival and angiogenesis. The aim of our study was to evaluate the impact of HIF-1a and CA IX (carbonic anhydrase IX) (one of its target genes) expression on prognosis and treatment outcome of patients with breast cancer. Because of the extreme O 2 -dependent instability of the protein, we first validated HIF-1a staining using xenograft tumours that were subjected to experimental conditions mimicking surgical clamping or sitting at room temperature under normoxic conditions after surgical excision but before fixation. Afterwards, the immunohistochemical staining of HIF-1a and CA IX was evaluated in 132 invasive breast carcinomas with a 10-year follow-up, and correlated to classical clinicopathological parameters and response to adjuvant therapy. No significant correlation was found between tumour size or nodal status and the expression of HIF-1a or CA IX. Statistically significant association was found between HIF-1a or CA IX staining and the grade, hormonal receptors loss and the presence of carcinoma in situ. Overexpression of HIF-1a and CA IX correlates with a poor prognosis in breast cancer. We show that HIF-1a is an independent prognostic factor for distant metastasis-free survival and disease-free survival in multivariate analysis. Furthermore, overexpression of HIF-1a or CA IX correlates with a poor outcome after conventional adjuvant therapy. CA IX is, however, a weaker prognostic and predictive factor than HIF-1a, and its association with HIF1a does not modify the survival curve neither response to therapy, compared to HIF-1a alone. ' 2007 Wiley-Liss, Inc.

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Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

Cited by 103 publications

References 25 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

Detection of carbonic anhydrase 9–expressing tumor cells in the lymph nodes of vulvar carcinoma patients by RT‐PCR

HIF‐1α and CA IX staining in invasive breast carcinomas: Prognosis and treatment outcome

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