Hedgehog signalling pathway and Carbonic Anhydrases in Breast cancer cell physiology

Breast cancer (BC) is one of the most diffused types of cancer worldwide. It affects predominantly women and is a highly curable disease if diagnosed at early stage. Several classifications of BC do exist according to different histopathological and molecular features. The worst subtype of BC are triple negative breast cancers (TNBCs) that do not express Estrogen (ER), Progesterone (PgR) and epidermal growth factor 2 (HER2) receptors consequently, these tumors are not sensitive to hormonal therapy. Nowadays, there is no specific clinical guideline approved, therefore, TNBCs treatment consists of cytotoxic agents and radiotherapy. The Hedgehog (Hh) pathway plays a pivotal role during the development of the organism and its expression is tightly controlled and normally kept silent in adult tissue. The Hh pathway indeed is reactivated for homeostasis maintenance after tissue injury or for the physiological tissue renewal. Deregulation of the Hh pathway is associated with development disturbs, underlining the relevance of its precise controlled expression. More and more Hh signalling is found to be involved in cancer development and progression. A growing body of literature underlines the correlation between the Hh pathway and bad prognosis for BCs. Indeed, the Hh pathway is normally silenced in normal breast epithelium and aberrantly activated in TNBCs, where it is associated with a more aggressive phenotype, enhancing proliferation, migration and invasion, furthermore, its activation is related to chemoresistant phenotypes of TNBCs. Carbonic anhydrases (CAs) are evolutionary conserved enzymes, mostly known for their role in pH regulation. CAs catalyze the reversible hydration of H2CO3 into CO2 and H2O. Several other roles have been described and attributed to CAs, from cell survival and migration, to the priming of the stem cell niche. Several CAs classes have been characterized and are conserved among the species. The classification is done according to the subcellular localization of CAs. Membrane bound CAs namely CAIX and CAXII, are overexpressed and active in cancer. While the role of CAIX is associated to bad prognosis, the role of CAXII has a contradictory outcome and still need to be elucidated. In BC, downregulation of CAXII reduced MDAMB231 cell migration through a reduction in p38 phosphorylation, while some researchers confer to the presence of this protein, a good prognostic value. We demonstrate for the first time a correlation between the Hh pathway and CAXII in controlling BCs pathology, emphasising how the activation of the Hh pathway is crucial in the control of CAXII expression, with consistent effects on cell proliferation, migration and invasion. Understanding the reciprocal regulation could be of main interest and should be taken into account in the design of new molecules to improve BC patient’s life expectancy.