TY - JOUR
T1 - Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast
AU - Wykoff, Charles C.
AU - Beasley, Nigel
AU - Watson, Peter H.
AU - Campo, Leticia
AU - Chia, Stephen K.
AU - English, Ruth
AU - Pastorek, Jaromir
AU - Sly, William S.
AU - Ratcliffe, Peter
AU - Harris, Adrian L.
N1 - Funding Information:
Supported by the Imperial Cancer Research Fund and the Wellcome Trust. P. H. W. is supported by a Scientist Award from the Medical Research Council of Canada, an Academic Award from the U. S. Army Medical Research and Materiel Command, and a Research Travel Fellowship from Burroughs Wellcome. S. K. C. is supported by the Shane Fellowship and the Canadian Breast Cancer Foundation.
PY - 2001
Y1 - 2001
N2 - Carbonic anhydrases (CA) influence intra- and extracellular pH and ion transport in varied biological processes. We recently identified CA9 and CA12 as hypoxia-inducible genes. In this study we examined the expression of these tumor-associated CAs by immunohistochemistry in relation to necrosis and early breast tumor progression in 68 cases of ductal carcinoma in situ (DCIS) (39 pure DCIS and 29 DCIS associated with invasive carcinoma). CA IX expression was rare in normal epithelium and benign lesions, but was present focally in DCIS (50% of cases) and in associated invasive carcinomas (29%). In comparison, CA XII was frequently expressed in normal breast tissues (89%), in DCIS (84%), and in invasive breast lesions (71%). In DCIS, CA IX was associated with necrosis (P = 0.0053) and high grade (P = 0.012). In contrast, CA XII was associated with the absence of necrosis (P = 0.036) and low grade (P = 0.012). Despite this, augmented CA XII expression was occasionally observed adjacent to necrosis within high-grade lesions. Neither CA IX nor CA XII expression was associated with regional or overall proliferation as determined by MIB1 staining. Assessment of mammographic calcification showed that CA XII expression was associated with the absence of calcification (n = 43, P = 0.0083). Our results demonstrate that induction of CA IX and CA XII occurs in regions adjacent to necrosis in DCIS. Furthermore, these data suggest that proliferation status does not influence expression of either CA in breast tissues, that hypoxia may be a dominant factor in the regulation of CA IX, and that factors related to differentiation, as determined by tumor grade, dominate the regulation of CA XII. The existence of differential regulation and associations with an aggressive phenotype may be important in the development of selective inhibitors of CAs, because the latter have recently been shown to prevent tumor invasion.
AB - Carbonic anhydrases (CA) influence intra- and extracellular pH and ion transport in varied biological processes. We recently identified CA9 and CA12 as hypoxia-inducible genes. In this study we examined the expression of these tumor-associated CAs by immunohistochemistry in relation to necrosis and early breast tumor progression in 68 cases of ductal carcinoma in situ (DCIS) (39 pure DCIS and 29 DCIS associated with invasive carcinoma). CA IX expression was rare in normal epithelium and benign lesions, but was present focally in DCIS (50% of cases) and in associated invasive carcinomas (29%). In comparison, CA XII was frequently expressed in normal breast tissues (89%), in DCIS (84%), and in invasive breast lesions (71%). In DCIS, CA IX was associated with necrosis (P = 0.0053) and high grade (P = 0.012). In contrast, CA XII was associated with the absence of necrosis (P = 0.036) and low grade (P = 0.012). Despite this, augmented CA XII expression was occasionally observed adjacent to necrosis within high-grade lesions. Neither CA IX nor CA XII expression was associated with regional or overall proliferation as determined by MIB1 staining. Assessment of mammographic calcification showed that CA XII expression was associated with the absence of calcification (n = 43, P = 0.0083). Our results demonstrate that induction of CA IX and CA XII occurs in regions adjacent to necrosis in DCIS. Furthermore, these data suggest that proliferation status does not influence expression of either CA in breast tissues, that hypoxia may be a dominant factor in the regulation of CA IX, and that factors related to differentiation, as determined by tumor grade, dominate the regulation of CA XII. The existence of differential regulation and associations with an aggressive phenotype may be important in the development of selective inhibitors of CAs, because the latter have recently been shown to prevent tumor invasion.
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U2 - 10.1016/S0002-9440(10)64048-5
DO - 10.1016/S0002-9440(10)64048-5
M3 - Article
C2 - 11238049
AN - SCOPUS:0035105565
SN - 0002-9440
VL - 158
SP - 1011
EP - 1019
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -