**9. Conclusion**

**6.4. AQP 5**

68 Tumor Metastasis

tissues [143].

Immunohistochemical analysis shows significant overexpression of AQP 5 in breast tumors from early breast cancer patients, and was correlated with the disease prognosis particularly in patients with ER/PR+ve tumors [142]. This observation was also confirmed by another group who showed that AQP 5 was not detectable in normal breast tissues, but was expressed mainly in the cell membrane of mammary carcinoma and associated with cellular differentiation, lymph node invasion and tumor stage [133]. The 5-year survival rate was decreased from 80% in AQP 5 −ve patients to 50% in AQP5+ve patients, suggesting that its expression was associ‐ ated with short overall survival [133]. In another report, AQP 5 expression was observed in the ductal epithelial cells of human breast tissues with significant overexpression in invasive compared to benign tumors [143]. It was also expressed in MCF7 and MDA-MB-231 breast cancer cell lines (at mRNA and protein level); shRNA, or hyperosmotic stress-induced reduction in AQP 5 expression significantly reduced cell proliferation and migration toward fetal bovine serum (FBS) gradient. Some reports have suggested that AQP 5 induces tumori‐ genesis (at least in lung epithelial cells) upon phosphorylation of the cAMP protein kinase

There is no clinical data so far which confirms the use of AQPs as diagnostic markers for breast cancer. However, many reports suggest a strong correlation between the expression profile of certain types of AQPs and breast cancer pathogenesis and prognosis. For example, AQP 1 expression was associated with poor clinical prognosis in ductal type, ER −ve and HER2/neu −ve breast cancer patients [132]. The cytoplasmic expression of AQP 1 was also correlated with advanced pathological features of invasive ductal carcinoma, lymph node metastasis and shorter survival [134]. Overexpression of AQP 3 in HER2-overexpressing patients [137] as well as in premenopausal ER+ve breast cancer patients [138] was associated with advanced stage. AQP 5 expression was also shown to be associated with poor clinical prognosis [133], partic‐ ularly in patients with ER/PR+ve tumors [142], and in the ductal epithelial cells of human breast

Detection of serum AQP 4 auto-antibodies has shown promising indication as a diagnostic tool in neuromyelitis optica (NMO), an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is claimed to be significantly associated with a higher number of relapses and longer disease duration [146, 147]. There are also reports suggesting a role for other AQPs: AQP 2 in determining the etiology of metabolic disorders dependent on the arginine vasopressin [148], AQP 3 in eczema [149] and AQP 4 in epilepsy [150].

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

consensus site located in its cytoplasmic loop [144, 145].

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

**7. AQPs: cancer diagnostic markers in breast cancer**

There is growing evidence in several tumors (including that of the breast) to indicate that several growth factors (e.g., EGF, VEGF and FGF-2) which are known to enhance cell invasion, may do so, at least in part, through increasing expression of a number of AQPs, suggesting a prometastatic role for these channels. This is likely to be mediated by interaction with various signaling molecules involved in cell invasion such as Ras, MAPK and PI3K, leading to rearrangement of the actin cytoskeleton (through interaction with RhoA/Rac), extracellular acidification (through interaction with LDH and HIF-1α, which by itself enhances cell invasion), enhanced secretion of proteolytic enzymes needed to degrade the extracellular matrix (ECM) (e.g., MMP2/9 and cathepsin B) and induction of the EMT process. AQPs also enhance cell invasion through a 'rounding' of the cell to enable it to squeeze through the ECM (termed amoeboidal motility). **Figure 2** summarizes the putative role of AQPs in cancer pathogenesis.

**Figure 2.** Role of AQPs in cancer pathogenesis. AQPs play an important role in cancer pathogenesis through enhance‐ ment of cancer cell proliferation, invasion and induction of epithelial to mesenchymal transition (EMT) as well as in‐ duction of amoeboidal motility. The mediators through which each AQP modulates these functions are elaborated in the scheme.
