**1. Introduction**

Breast cancer remains the leading cause of tumor-associated mortality in women worldwide. Estrogen, acting through predominantly nuclear-located receptors (ER), has a significant

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detrimental impactduring its pathogenesis [1].This forms the basis for endocrine therapy, with the application of pharmacological antagonists generally termed selective estrogen receptor modulators, such as tamoxifen. These have resulted in significant improvements in quality of life as well as improved prognosis [2] in a significant proportion of patients with clinically defined ER+ve status [3]. Unfortunately, *de novo* resistance to tamoxifen occurs in about 30– 40% of patients (those with very low level of ER expression, clinically designated as ER−ve) and even in about 50% of the clinically defined ER+ve patients. Furthermore, almost all initially responsive patients with late stage metastatic disease eventually relapse due to the develop‐ ment of *acquired* resistance to anti-estrogen therapy. These forms of endocrine resistance invariably lead to a more aggressive form of resurgent disease [4], and occur in parallel with cellular transition from epithelial to mesenchymal phenotype (EMT). There is a strong associ‐ ation between the EMT process and metastasis, which involves detachment of individual epithelial cells from neighboring cells, loss of polarity, scattering, acquisition of enhanced motility and invasion into the extracellular matrix (ECM) before entering blood and lymphat‐ ic vessels. Many phenotypic changes occur during this process which includes the loss of cellcell adhesion as a result of reduced E-cadherin and catenins expression in adherens junctions, reducedclaudins andoccludins expressionattightjunctions andreducedexpressionof various epithelial cytokeratins such as KRT8, 18 and 19 which presumably aids in disruption of cytoskeletal connections that maintain tissue architecture. These changes are also paralleled withup-regulationofmesenchymalmarkerssuchasvimentin,fibronectin,alphasmoothmuscle actin (ACTA2), N-cadherin and various matrix metalloproteinases (MMPs) [4, 5]. Attempts to overcome endocrine resistance include the use of pure estrogen antagonists such as fulves‐ trant (in place of tamoxifen, which is associated with some agonist actions with prolonged administration) or agents which inhibit peripheral extragonadal synthesis of estrogen (aroma‐ tase inhibitors such as anastrazole), which delays but does not resolve this problem [6, 7]. In addition, receptor tyrosine kinase (RTK) inhibitors have been used recently in the treatment of endocrine-resistant breast cancer [8], but they have limitations in terms of target specificity and clinical outcomes. For example, the reversible inhibitor of epidermal growth factor receptor (EGFR) erlotinib also blocks ERBB2 [9, 10], AKT (the downstream target of phosphatidylinosi‐ tide 3-kinases; PI3K) and mitogen-activated protein kinase (MAPK) phosphorylation in breast cancer cells [11]. Furthermore, imatinib inhibits the activity of the tyrosine kinase domain of various targets such as ABL, KIT and platelet-derived growth factor receptor (PDGFR) [12, 13]. The lack of specificity of these agents might increase the risk of side effects and therefore limits their clinical usage and utility. Since the current therapeutic options for endocrine insensitive breast cancer patients have various limitations (including severe side effect profile and resistance),there isaneedtofindbettertherapeutic targets tocontrolthis conditionandimprove its prognosis.

Aquaporins (AQPs) represent a family of 13–14 small hydrophobic integral transmembrane water channel proteins which are widely distributed in various tissues in the body. Their function is to transport mainly water (through passive transport), glycerol, solutes (such as urea, carbon dioxide, ammonia and nitric oxide) [14–20], as well as larger polar solutes (such as sugars and hydrogen peroxide) [21–23]. The first discovered family member of these proteins was initially called CHIP28, but it is now known as AQP 1 [24, 25]. AQPs are classified on the basis of their substrate permeability: (a) the classical water permeable AQPs 0, 1, 2, 4, 5, 6 and 8; (b) the water and small solute (e.g., glycerol and urea) permeable aquaglyceroporins AQPs 3, 7, 9, 10 and 12; (c) gas (carbon dioxide and nitric oxide) and ammonia permeable AQPs 1, 4 and 5; and (d) small ion (e.g., sodium and potassium) conducting AQP 1 [25]. Besides their main role in maintaining salt and water homeostasis, recent evidence suggests their involve‐ ment in various disease conditions including neoplasms such as breast cancer. These mem‐ brane channels have received much attention in recent years as potential novel drug targets for reducing cancer angiogenesis and metastasis. This chapter will provide evidence from recent studies regarding the involvement of various AQPs in breast cancer pathogenesis and will highlight their role in disease diagnosis, prognosis and treatment.
