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- STEAP1 is overexpressed in prostate cancer and prostatic intraepithelial neoplasia lesions, and it is positively associated with Gleason scorePublication . Gomes, Inês; Arinto, Patrícia; Lopes, Carlos; Santos, Cecilia; Baptista, CláudioSix transmembrane epithelial antigen of the prostate 1 (STEAP1) is a transmembrane protein of epithelial cells, mostly located at cell-cell junctions, and is overexpressed in several types of tumors, particularly prostate cancer. Several studies have pointed STEAP1 as a biomarker, but the clinical significance of its overexpression is not fully understood. Therefore, we aimed to establish the association of STEAP1 immunoreactivity with histologic diagnosis and clinical data of patients.
- Characterization of oligoadenylate synthetase-1 expression in rat mammary gland and prostate: effects of 17beta-estradiol on the regulation of OAS1g in both tissuesPublication . Maia, C J; Socorro, Sílvia; Schmitt, Fernando; Santos, CecíliaOAS1 belongs to a protein family of interferon-induced enzymes characterized by their ability to catalyze the synthesis of 2'-5'-linked oligomers of adenosine from ATP (2-5A). 2-5A bind to the latent Ribonuclease L (RNase L), which subsequently dimerizes into the active form, acquiring the capacity of cleaving cellular and viral mRNA. Several studies indicate that OAS1 is an important inducer of apoptosis in human cancer cells and that it may be regulated by 17beta-estradiol (E(2)). The aim of this study was to characterize OAS1 gene expression in rat mammary gland and prostate, and to analyze its regulation by E(2) in both tissues. It is demonstrated that OAS1g is the most abundant OAS1 gene expressed in both tissues, and that OAS1 protein is present in the nucleus of rat mammary gland and prostate epithelial cells. In addition, it is shown by Real Time PCR that OAS1g is up-regulated by E(2) in rat mammary gland, but down-regulated in prostate, suggesting that the OAS1g gene may be related to estrogen dependent pathways in rat mammary gland and prostate physiology.
- Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesisPublication . Marques, Ricardo; Vaz, Cátia; Baptista, Cláudio; Gomes, Madalena; Gama, Adelina; Alves, Gilberto; Santos, Cecilia; Schmitt, Fernando; Socorro, SílviaRegucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland.
- STEAP1 is over-expressed in breast cancer and down-regulated by 17β-estradiol in MCF-7 cells and in the rat mammary glandPublication . Maia, C J; Socorro, Sílvia; Schmitt, Fernando; Santos, CeciliaSix transmembrane epithelial antigen of the prostate 1 (STEAP1) was identified as a prostate-specific cell-surface antigen over-expressed in prostate cancer, and in human cancer cell lines obtained from several other tissues. Its cell surface location in all tumor types analyzed so far, and its absence in most vital organs in humans, turned STEAP1 into a potential target for anti-tumor immunotherapy. This study provides experimental evidence that STEAP1 is also over-expressed in human breast cancer cases, and in normal breast tissue adjacent to breast tumors, where it is localized in the cell membrane of epithelial cells. It is also demonstrated that STEAP1 transcription correlates negatively with estrogen receptor (ER) immunoreactivity, and positively with tumor grading in breast cancer cases. As estrogens are involved in breast cancer onset and progression, the response of STEAP1 to 17beta-estradiol (E2) was investigated in the mammary gland of rats, and in the human breast cancer cell line, MCF-7. These experiments demonstrated that STEAP1 is down-regulated by E2 in both models. The mechanisms underlying the STEAP1 response to E2 in vitro were further investigated in MCF-7 cells, and the results obtained suggest an effect mediated by the membrane-bound ERalpha (mbERalpha).
- Six transmembrane epithelial antigen of the prostate 1 is down-regulated by sex hormones in prostate cellsPublication . Gomes, Inês; Santos, Cecilia; Socorro, Sílvia; Baptista, CláudioSTEAP1 is over-expressed in several types of tumors, especially prostate cancer, where it is localized in the plasma membrane of epithelial cells, at cell-cell junctions. Its role in prostate carcinogenesis and its regulation in prostate cells remain unknown. Therefore, we propose to study the effect of sex hormones in the regulation of STEAP1 expression in prostate cells in vitro and in vivo.
- Expression of STEAP1 and STEAP1B in prostate cell lines, and the putative regulation of STEAP1 by post-transcriptional and post-translational mechanismsPublication . Gomes, Inês; Santos, Cecilia; Baptista, CláudioSTEAP1 gene is overexpressed in several kinds of tumors, particularly in prostate cancer. Besides STEAP1, there is another related gene, STEAP1B, which may encode two different transcripts. Although several studies have been pointing STEAP1 as a putative immunotherapeutic target and biomarker, the mechanisms underlying its regulation are not fully understood. In silico analysis allowed us to show that STEAP1 and STEAP1B share high homology, but with slight differences at structural level. Experiments with prostate cells showed that STEAP1B2 is overexpressed in cancer cells. Regarding STEAP1 regulation, it is demonstrated that the stability of mRNA and protein is higher in LNCaP than in PNT1A cells. Of note, serum triggered opposite effects in LNCaP and PNT1A in relation to STEAP1 stability, e.g., increasing it in PNT1A and decreasing in LNCaP. These results suggest that STEAP1 may be regulated by post-transcriptional and post-translational modifications (PTM), which may differ between non-neoplastic and neoplastic cells. These PTM are supported through in silico analysis, where several modifications such as N-glycosylation, N-Glycation, Phosphorylation and O-linked β-N-acetylglucosamine, may occur in STEAP1 protein. In conclusion, these data indicate that STEAP1B2 is overexpressed in neoplastic cells, and PTM may be involved in regulation of STEAP1 expression in prostate cells.
- Regucalcin is under-expressed in human breast and prostate cancers: Effect of sex steroid hormonesPublication . Maia, C J; Santos, Cecília; Schmitt, Fernando; Socorro, SílviaRegucalcin 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.
- STEAP Proteins: From Structure to Applications in Cancer TherapyPublication . Gomes, Inês; Maia, C J; Santos, CeciliaThe 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.
- The sex bias of cancerPublication . Costa, Ana Raquel; Cruz, Inês; Oliveira, Mariana Lança de; Gonçalves, Isabel; Cascalheira, José; Santos, CeciliaIn cancers of hormone-dependent organs like women breast and reproductive organs, endometrium and ovaries, and men’s prostate and testicular cancer, the roles of sex hormones and deregulation of hormone axes are well-documented. More strikingly, epidemiological data highlights significant differences between sexes in the incidence of various cancers in non-reproductive organs, where the role of sex hormones has been less studied. In an era when personalised medicine is gaining recognition, understanding molecular, cellular and biological differences between men and women is timely for developing more appropriate therapeutic interventions according to gender. In this review we show that sex hormones also shape much of the deregulated cellular and molecular pathways leading to cell proliferation and cancer in nonreproductive organs.
- STEAP1 (Six Transmembrane Epithelial Antigene of the Prostate 1)Publication . Santos, Cecilia; Socorro, Sílvia; Maia, C J339 amino acids (NCBI: AF186249); MW 40 kDa, contains 6 transmembrane helical domains (table 1) and a theoretical pI of 9.28.