Targeting metallothionein for prognosis and treatment of breast cancer.

Breast cancer is a disease that has plagued many women globally. The rapid rise in the incidence rate has prompted the rigorous search to understand its etiology and find better management strategies for this disease. Metallothionein (MT) belongs to a family of metal-binding proteins where dysregulated expression of this protein has been observed in invasive breast ductal carcinomas. Since its discovery in equine kidney, functions of MT have extended beyond the initial role of heavy metal detoxification to promoting tumorigenesis. MT, which was reported to be highly expressed in many tumors including breast cancers, is known to regulate key processes such as cell proliferation, apoptosis and even chemoresistance. In this patent review, we shall evaluate the roles of 10 functional isoforms of MT in breast neoplasia and discuss the utility of MT isoforms as biomarkers for prognosis. Strategies targeting MT for treatment could provide alternatives to overcome this dreaded disease which has claimed the lives of many women.

Modulation of metallothionein isoforms is associated with collagen deposition in proliferating keloid fibroblasts in vitro.

The keloid fibroblast (KF) is known to have higher proliferative capacity than normal dermal fibroblast (NF). Metallothionein (MT), a metal-binding protein, has been reported to promote cell proliferation. In this study, we evaluated the expression of MT isoforms at the mRNA level in fetal bovine serum (FBS)-stimulated proliferating KF. Although the morphological appearance of NF and KF was similar when viewed under light, confocal and transmission electron microscopy, there was surprisingly a generally lower expression of MT isoforms in KF when compared with NF and also reduced MT staining in dermal fibroblasts of keloids as opposed to normal skin. Primary cultures of KF grown in 5% FBS or 10% FBS compared to without FBS demonstrated significantly higher proliferative activity and more abundant deposition of collagen. Contrary to expectation, MT-1A, -1F, -1G, -1X and -2A isoforms were significantly down-regulated in proliferating KF. Moreover, stimulating KF with TGF ß1, which is known to promote collagen synthesis and keloid formation, increased expression of Collagen 1A and 3A genes accompanied by reduction in MT-2A gene expression. Furthermore, down-regulation of the MT-2A gene in proliferating KF by siRNA-mediated silencing enhanced cell proliferation with concomitant up-regulation of the NF-κB gene and 10 of 13 other NF-κB pathway-related genes analysed but no alteration of the Collagen 1 and Collagen 3 gene expression. It would appear that down-regulation of MT isoforms in proliferating KF, in particular MT-2A, enhances keloidogenesis with the possible involvement of the NF-κB signalling pathway.

Heat shock proteins as novel therapeutic targets in cancer.

Heat shock proteins (HSPs) are evolutionarily conserved molecules synthesised by cells exposed to sub-lethal stresses. Acting as molecular chaperones, HSPs protect cells from environmental stress damage by assisting in proper folding and stabilisation of proteins. In addition, they help to sequester severely damaged proteins for degradation. Owing to the nature of their function, HSPs are often found to be overexpressed in a wide range of cancers. Members of the HSP family have been implicated in cancer growth as promoting tumour cell proliferation as well as inhibiting cellular death pathways. In recent years, several HSP90 client proteins have been validated as clinically important therapeutic targets for treatment of cancer, and inhibitors of HSP90 have emerged as potentially beneficial anticancer agents. This review explores the involvement of HSPs in cancer and the development of several anticancer agents with promising therapeutic applications.