The human 6-transmembrane epithelial antigen of prostate (STEAP) family comprises STEAP1, STEAP2, STEAP3, and STEAP4. All of these proteins are unique to mammals and share an innate activity as metalloreductases, indicating their importance in metal metabolism. Overall, they participate in a wide range of biologic processes, such as molecular trafficking in the endocytic and exocytic pathways and control of cell proliferation and apoptosis. STEAP1 and STEAP2 are overexpressed in several types of human cancers, namely prostate, bladder, colon, pancreas, ovary, testis, breast, cervix, and Ewing sarcoma, but their clinical significance and role in cancer cells are not clear. Still, their localization in the cell membrane and differential expression in normal and cancer tissues make STEAP proteins potential candidates as biomarkers of several cancers, as well as potential targets for new immunotherapeutic strategies for disease attenuation or treatment. This review brings together the current knowledge about each STEAP protein, giving an overview of the roles of this family of proteins in human physiology and disease, and analyzes their potential as immunotherapeutic agents in cancer research. Mol Cancer Res; 10(5); 573-87. Ó2012 AACR. IntroductionThe 6-transmembrane epithelial antigen of prostate (STEAP) family of proteins includes 4 members, named 6-transmembrane epithelial antigen of prostate 1 to 4 (STEAP1-STEAP4). They all have in common a 6-transmembrane domain, a COOH-terminal domain with significant homology to the yeast FRE family of b-type cytochrome metalloreductases, and an N-terminal with homology to the archaeal and bacterial F 420 H 2 :NADP

Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-L-thyronine.

Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid hormones and vitamin A. So far, TTR has only been found in vertebrates, of which piscine TTR displays the lowest sequence identity with human TTR (47%). Human and piscine TTR bind both thyroid hormones 3,5,3-triiodo-L-thyronine (T 3 ) and 3,5,3,5-tetraiodo-L-thyronine (thyroxine, T 4 ). Human TTR has higher affinity for T 4 than T 3 , whereas the reverse holds for piscine TTR. X-ray structures of Sparus aurata (sea bream) TTR have been determined as the apo-protein at 1.75 Å resolution and bound to ligands T 3 and T 4 , both at 1.9 Å resolution. The apo structure is similar to human TTR with structural changes only at ␤-strand D. This strand forms an extended loop conformation similar to the one in chicken TTR. The piscine TTR⅐T 4 complex shows the T 4 -binding site to be similar but not identical to human TTR, whereas the TTR⅐T 3 complex shows the I3 halogen situated at the site normally occupied by the hydroxyl group of T 4 . The significantly wider entrance of the hormone-binding channel in sea bream TTR, in combination with its narrower cavity, provides a structural explanation for the different binding affinities of human and piscine TTR to T 3 and T 4 .

Regucalcin plays an important role in maintenance of intracellular Ca(2+) homeostasis, suppresses cell proliferation, inhibits expression of oncogenes, and increases the expression of tumour suppressor genes. This suggests that regucalcin functions may be altered in cancer tissues. In this study the regucalcin expression in breast and prostate cancer cases was analysed by RT-PCR and immunohistochemistry showing that the mRNA and/or protein are under-expressed in these tumors. The effect of sex steroid hormones on regucalcin expression in breast and prostate cancer cells was determined by real-time PCR. MCF-7 and LNCaP cells were stimulated with 0, 1, and 10 nM of 17beta-estradiol (E(2)) or 5alpha-dihydrotestosterone (DHT), respectively, for 0, 6, 12, 24, and 48 h. MCF-7 cells were also stimulated with E(2) conjugated to BSA (E(2)-BSA). To explore the mechanisms underlying the sex steroid regulation of regucalcin expression, control treatments with ICI 182,780, flutamide and cyclohexamide were carried out. E(2) effects regulating regucalcin expression were not abrogated in the presence of ICI 182,780, and were similar to those observed with E(2)-BSA, which suggests the involvement of a membrane-bound estrogen receptor. In LNCaP cells, DHT down-regulated regucalcin expression, an effect inhibited by the presence of both flutamide and cyclohexamide, suggesting the involvement of androgen receptor and de novo protein synthesis. The loss of regucalcin expression in breast and prostate cancer cases and the regulation of its expression by sex steroid hormones suggest that it may be associated with development and progression of these human tumors.

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