Depletion of carbonic anhydrase IX abrogates hypoxia-induced overexpression of stanniocalcin-1 in triple negative breast cancer cells.

Carbonic anhydrase IX (CAIX) is a pH-regulating enzyme that plays a key role in maintaining an alkaline intracellular pH under hypoxic conditions. It is overexpressed in a variety of solid cancers, including breast cancer (BC), and has been implicated in the migration, invasion and stemness of breast cancer cells. Therefore, CAIX recently emerged as a novel therapeutic target for the treatment of BC. To gain an insight into the mechanism of action of CAIX inhibitors, we investigated the impact of CAIX knock-down on the transcriptional response to hypoxia in 2 BC cell lines - MCF7 and MDA-MB-231, by performing a global gene expression analysis. This showed that CAIX knock-down had a relatively minor effect on the global transcriptional response to hypoxia, however it blocked hypoxia-induced upregulation of stanniocalcin-1 (STC1), a secreted glycoprotein that has been shown to promote tumor progression and metastasis in BC. Kaplan-Meier survival analysis showed that high STC1 expression is significantly associated with poor survival in patients with basal-type breast cancer but not luminal A and HER2+ subtypes. Moreover, the association was particularly high in a subgroup of basal-type BC patients with TP53 mutations thus revealing a putative cooperation of STC1 with mutated TP53 in generating highly aggressive BC subgroup. Taken together, these findings show that CAIX inhibitors at least partially act through blocking STC1 induction in BC cells and reveal a subgroup of BC patients, who potentially would benefit most from the treatment with CAIX inhibitors.