CAIX, has been linked to poor prognosis and survival of breast cancer patients. Expression of CAIX is low in normal breast tissue or benign lesions, but strongly expressed in 50% of all ductal carcinoma in situ (DCIS) of the breast, and in 38% of DCIS associated with invasive disease and is present mainly in abnormal epithelium in breast carcinoma. The CAIX transmembrane protein consists of a proteoglycan-like domain and an intracellular carboxy terminal tail which can influence cell-cell adhesion, and catalyzes the reversible reaction CO2 + H2O → H+ + HCO3?. This production of protons acidifies the tumor microenvironment, while bicarbonate ions are transported into the cell maintaining an alkaline intracellular pH, which may inhibit apoptosis. Hypoxia increases expression of metalloproteinases in breast and other cancer cells; these enzymes are activated in acidic conditions causing destruction of basement membrane components thus enhancing the ability of tumor cells to metastasize. Similarly, cell migration depends on acidic conditions in lamellipodia, which are partially produced by activation of CAIX and its interaction with bicarbonate transporters. Since the acidic/hypoxic conditions in the tumor microenvironment facilitate tumor progression, CAIX plays an important part in the acidification of the tumor environment and tumor metastasis. Metastatic growth is associated with epithelial to mesenchymal transition (EMT) and is strongly linked to loss of E-cadherin because hypoxia activates the lysyl oxidase-Snail pathway which represses E-cadherin expression. Furthermore, CAIX is known to impede E-cadherin mediated cell adhesion by decreasing the amount of E-cadherin bound to the cytoskeleton . Recent studies also demonstrate that CAIX enhances the metastatic potential of tumor cells by a mechanism associated with decreased Rho-GTPase activity leading to EMT.
Ward C, Meehan J, Mullen P, et al. Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series of in vitro breast cancer models. Oncotarget. 2015;6(28):24856-24870.