Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast

Carbonic anhydrases (CA) influence intra- and extracellular pH and ion tran sport in varied biological processes. We recently identified CA9 and CA12 a s hypoxia-inducible genes. In this study we examined the expression of thes e tumor-associated CAs by immunohistochemistry in relation to necrosis and early breast tumor progression in 68 cases of ductal carcinoma in situ (DCI S) (39 pure DCIS and 29 DCIS associated with invasive carcinoma). CA IX exp ression was rare in normal epithelium and benign lesions, but was present f ocally 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 contras t, CA XII was associated with the absence of necrosis (P = 0.036) and low g rade (P = 0.012). Despite this, augmented CA XII expression was occasionall y observed adjacent to necrosis within high-grade lesions. Neither CA IX no r CA XII expression was associated with regional or overall proliferation a s determined by MIB1 staining, Assessment of mammographic calcification sho wed 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 d ata suggest that proliferation status does not influence expression of eith er CA in breast tissues, that hypoxia may be a dominant factor in the regul ation of CA IX, and that factors related to differentiation, as determined by tumor grade, dominate the regulation of CA XII, The existence of differe ntial regulation and associations with an aggressive phenotype may be impor tant in the development of selective inhibitors of CAs, because the latter have recently been shown to prevent tumor invasion.