Human 3ß-hydroxysteroid dehydrogenase type 1 in human breast cancer: clinical significance and prognostic associations.

Active sex steroids including estrogens and androgens are locally produced from circulating inactive steroids by various steroid-metabolizing enzymes, and play pivotal roles in the progression of hormone-dependent breast cancers. Human 3ß-hydroxysteroid dehydrogenase type 1 (3ß-HSD type 1) is a critical enzyme in the formation of all classes of active steroid hormones, and is also involved in the inactivation of potent androgen dihydrotestosterone (DHT). Therefore, this enzyme is suggested to modulate active sex steroid production or inactivation, with a role in hormone-dependent breast cancer. The purpose of this study was to investigate the clinical significance of 3ß-HSD type 1 in human breast cancer. Using immunohistochemistry (IHC), we evaluated 3ß-HSD type 1 expression in 161 human breast cancers and analyzed correlations of 3ß-HSD type 1 expression with various clinicopathological factors. Of 161 breast cancer cases, 3ß-HSD type 1 expression in cancer cells was detected in 119 cases (73.9%), and was positively correlated with estrogen receptor (ER)-positivity but not HER-2 status. In ER-positive cases (n = 130), 3ß-HSD type 1 expression was inversely correlated with invasive tumor size (P = 0.0009), presence of invasive region (P = 0.0107), and lymphatic involvement (P = 0.0004). 3ß-HSD type 1 expression was significantly associated with decreased risk of recurrence or improved prognosis by both univariate (P = 0.0003 and P = 0.009, respectively) and multivariate (P = 0.027 and P = 0.023, respectively) analyses. Our findings indicate that this enzyme is a prognostic factor in hormone-dependent breast cancer.

Reduced glycosylation of α-dystroglycans on carcinoma cells contributes to formation of highly infiltrative histological patterns in prostate cancer.

BACKGROUND: α-Dystroglycan (DG) carries glycan chains that bind to laminin and thus function in homeostasis of not only skeletal muscle but also of various epithelial cells. Loss of glycosylation has been suggested to play important roles in tumor development, particularly in detachment and migration of carcinoma cells. We previously reported that glycosylation of α-DG, but not levels of α-DG core protein itself, is reduced in prostate carcinoma. In this study, we investigate the association between reduction of laminin-binding glycans on α-DG and the degree of tumor cell differentiation and/or infiltrative properties, as assessed by the Gleason grading system. METHODS: Immunohistochemical analysis of 146 biopsy specimens of prostate adenocarcinoma with various Gleason scores was carried out employing IIH6 and 6C1 antibodies, which recognize laminin-binding glycans on α-DG and α-DG core proteins, respectively. Double immunofluorescence staining was performed to evaluate colocalization of α-DG and laminin, and to determine which types of epithelial cells express laminin-binding glycans on α-DG. RESULTS: Reduction of α-DG glycosylation, rather than loss of α-DG core protein, was correlated with higher Gleason patterns. Reduction was most conspicuous at the interface between carcinoma cells and the basement membrane. In addition, in non-neoplastic prostate glands, laminin-binding glycans were expressed predominantly on the basolateral surface of basal cells. CONCLUSIONS: Reduced expression of laminin-binding glycans on α-DG may contribute to formation of highly infiltrative behavior of prostate carcinoma cells. Substantial reduction of laminin-binding glycans in carcinoma tissue could be partly ascribed to disappearance of pre-existing basal cells.

Prominent expression of sialyl Lewis X-capped core 2-branched O-glycans on high endothelial venule-like vessels in gastric MALT lymphoma.

High endothelial venule (HEV)-like vessels have been observed in gastric B cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma), as well as in its preceding lesion, chronic Helicobacter pylori gastritis. Previously we reported that glycans on HEV-like vessels in the latter lesion served as L-selectin ligands, although their function is unclear. We have investigated sialyl Lewis X (sLeX)-related glycoepitopes and found that MECA-79(-) /HECA-452(+) /NCC-ST-439(+) HEV-like vessels preferentially mark gastric MALT lymphoma compared to chronic H. pylori gastritis. We then constructed CHO cell lines expressing potential MECA-79(-) /HECA-452(+) /NCC-ST-439(+) glycans, as well as other sLeX-type glycans, on CD34 and evaluated L-selectin binding to those cells, using L-selectin-IgM chimera binding and lymphocyte adhesion assays. L-selectin-IgM chimeras bound to CHO cells expressing 6-sulpho-sLeX attached to core 2-branched O-glycans with or without 6-sulpho-sLeX attached to extended core 1 O-glycans, but only marginally to other CHO cell lines. By contrast, CHO cells expressing 6-sulpho-sLeX attached to extended core 1 and/or core 2-branched O-glycans, as well as non-sulphated sLeX attached to core 2-branched O-glycans, showed substantial lymphocyte binding, while binding was negligible on lines expressing 6-sulpho- and non-sulphated sLeX attached to N-glycans and non-sulphated sLeX attached to extended core 1 O-glycans. These results indicate that MECA-79(-) /HECA-452(+) /NCC-ST-439(+) glycans, specifically, 6-sulpho- and non-sulphated sLeXs attached to core 2-branched O-glycans, expressed on HEV-like vessels in gastric MALT lymphoma function as L-selectin ligands and likely contribute to H. pylori-specific T cell recruitment in the progression of gastric MALT lymphoma.

Leydig cell tumor and malignant lymphoma in a patient with nonclassical 21-hydroxylase deficiency.

A 46-year-old man was admitted in our hospital with hypoglycemia; his FPG was 43 mg/mL. Five years earlier, he underwent simultaneous surgeries for an adrenal adenoma, a benign Leydig cell tumor (LCT), and a malignant lymphoma. Based on the laboratory results, he was diagnosed as congenital adrenal hyperplasia (CAH) due to nonclassical 21-hydroxylase deficiency (21-OHD). On immunohistochemistry analysis using the antibody against adrenal-specific 11beta-hydroxylase antibody, the LCT showed both properties as a testicular cell and as an adrenal cell. The genetic background of 21-OHD might contribute to the development of malignant lymphoma. Such as a case of LCT and malignant lymphoma in a patient with 21-OHD seems to be rare.