**8. AQPs: therapeutic targets for breast cancer**

There appears to be potential for the use of AQP-based therapies (such as cysteine-reactive heavy metal-based inhibitors, AQP-induced water permeation, monoclonal AQP-specific antibodies and AQP gene transfer) to treat various conditions including breast cancer. Several heavy metals have been shown to inhibit AQP 1. These include mercury II chloride (through covalent interaction with the Cys189 residue in the water pore of AQP 1) [151, 152] and silver and gold III compounds (through interaction with the cysteine residue near the conserved NPA domain) [153, 154]. Gold III compounds were also shown to inhibit AQP 3 through interaction with the Cys40 in its extracellular domain [154, 155]. Other nonmetal containing small molecule inhibitors include tetraethylammonium (TEA+ ), which reversibly inhibits AQP 1 through interaction with the Tyr186 site [156, 157]. The carbonic anhydrase inhibitor acetazolamide was also shown to inhibit AQPs 1 and 4 [158, 159]. Several antiepileptics, and the loop diuretic bumetanide, are reported to inhibit AQP 4 [159–161]. The other loop diuretic furosemide was also found to inhibit AQP 1 [162]. Furthermore, AQP gene transfer therapy is also in its early phases; AQP 1 cDNA transfer into the parotid glands for treating salivary gland hypofunction after radiation therapy is currently in phase I clinical trials [163–165].

In noncancerous conditions, some AQPs (1–4 and 7) are required for the formation of concen‐ trated urine, which suggests that AQP-inhibitors might act as a unique form of diuretics to treat various disorders such as heart failure [87, 88]. Increased expression of AQP 4 exacerbated water accumulation in the brain, suggesting that AQP 4 inhibitors might be used to treat cytotoxic edema [90, 91]. Other potential therapeutic uses of AQP-therapies include treatment of various exocrine disorders, obesity and glaucoma [166].

AQP 1 is expressed on the endothelial cells of microvessels in various tumors including the breast [167], with a clear role in mediating angiogenesis and invasion through interaction with the actin cytoskeletal machinery, EGF, VEGF and HIF-1α. It has been suggested that the carbonic anhydrase inhibitor acetozolamide, and the antiepileptic drug topiramate, suppress tumor invasion in part through inhibiting AQP 1 gene expression [168, 169]. AQP 3 was also shown to be involved in breast cancer cell invasion through interaction with the actin cytos‐ keleton proteins, ER, chemokines and growth factors (CXCL-12, FGF-2), downstream signaling molecules (ERK1/2, Akt, PTEN and PTP1B) and induction of the EMT process. Furthermore, AQP 5 also enhanced breast cancer invasion in part through interaction with cAMP. The chemotherapeutic drug cisplatin inhibits the expression of AQP 5 in ovarian cancer and leads to reduced lymph node metastasis [170]. Therefore [171], inhibitors of the above-mentioned AQPs may have potential applications in breast cancer therapy through their inhibitory actions on tumor angiogenesis and invasion.
