Androgens control spermatogenesis, but germ cells themselves do not express a functional androgen receptor (AR). Androgen regulation is thought to be mediated by Sertoli and peritubular myoid cells, but their relative roles and the mechanisms involved remain largely unknown. Using Cre͞loxP technology, we have generated mice with a ubiquitous knockout of the AR as well as mice with a selective AR knockout in Sertoli cells (SC) only. Mice with a floxed exon 2 of the AR gene were crossed with mice expressing Cre recombinase ubiquitously or selectively in SC (under control of the anti-Mü llerian hormone gene promoter). AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted. In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract. Expression of the homeobox gene Pem, which is androgen-regulated in SC, was severely decreased. Testis weight was reduced to 28% of that in WT littermates. Stereological analysis indicated that the number of SC was unchanged, whereas numbers of spermatocytes, round spermatids, and elongated spermatids were reduced to 64%, 3%, and 0% respectively of WT. These changes were associated with increased germ cell apoptosis and grossly reduced expression of genes specific for late spermatocyte or spermatid development. It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte͞spermatid development͞ survival critically depends on androgens.

A B S T R A C T The influence of the serum binding protein (DBP) for vitamin D and its metabolites on the concentration of its main ligands, 25-hydroxyvitamin D3 (25-OHD3) and 1,25-dihydroxyvitamin D3 (1,25-[OHh2D3) was studied. The concentration of both 1,25-(OH)2D3 and DBP in normal female subjects (45±14 ng/liter and 333±58 mg/liter, mean+SD, respectively; n = 58) increased during the intake of estro-progestogens (69±27 ng/liter and 488±90 mg/liter, respectively; n = 29), whereas the 25-OHD3 concentration remained unchanged. A positive correlation was found between the concentrations of 1,25-(OH)2D3 and DBP in these women.At the end of pregnancy, the total concentrations of 1,25-(OH)2D3 (97±26 ng/liter, n = 40) and DBP (616 ±84 mg/liter) are both significantly higher than in nonpregnant females and paired cord serum samples (48±11 ng/liter and 266±41 mg/liter, respectively). A marked seasonal variation of 25-OHD3 was observed in pregnant females and their infants, whereas in the same samples the concentrations of both DBP and 1,25-(OH)2D3 remained constant throughout the year.The free 1,25-(OH)2D3 index, calculated as the molar ratio ofthis steroid and DBP, remains normal in women taking estro-progestogens, however, and this might explain their normal intestinal calcium absorption despite a high total 1,25-(OH)2D3 concentration. In pregnancy the free 1,25-(OH)2D3 index remains normal up to 35 wk of gestation, but during the last weeks of Part of this work was presented at

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The expression of fatty acid synthase (FAS), a key lipogenic enzyme and potential target for antineoplastic therapy, was analyzed in 87 frozen needle biopsies of prostate cancer using a highly sensitive immunohistochemical detection technique (Envision). In comparison to normal or benign, hyperplastic glandular structures, which were all negative for FAS staining, immunohistochemical signal was evident in 24/25 low grade prostatic epithelial neoplasia (PIN) lesions, in 26/26 high grade PIN lesions and in 82/87 invasive carcinomas. Staining intensity tended to increase from low grade to high grade PIN to invasive carcinoma. Cancers with a high FAS expression had an overall high proliferative index. No correlation was found between FAS expression and lipid accumulation. These findings indicate that increased FAS expression is one of the earliest and most common events in the development of prostate cancer, suggesting that FAS may be used as a general prostate cancer marker and that antineoplastic therapy based on FAS inhibition may be an option for chemoprevention or curative treatment for nearly all prostate cancers. © 2002 Wiley-Liss, Inc. Key words: fatty acid synthase; lipogenesis; cancer development; tumor marker Development and progression of cancer is commonly viewed as a multistep process reflecting genetic alterations that drive the progressive transformation of normal cells into highly malignant ones. In the case of prostate cancer, which characteristically develops as a multifocal and heterogeneous lesion, it has been difficult to find common alterations that mark discrete steps in its development. One of the molecular changes reported in various cancers, is overexpression of Oncogenic Antigen-519 (OA-519), 1 OA-519 is the marker designation for a protein sharing epitopes with a haptoglobin-related protein (hrp), found to be overexpressed in breast cancers with a higher risk for tumor recurrence. 1 Subsequent characterization of this protein revealed that it corresponds to fatty acid synthase (FAS), a key metabolic enzyme that plays a central role in the de novo biosynthesis of fatty acids. 2 The preferential expression of FAS in cancer cells has sparked studies to exploit FAS as a potential target for antineoplastic therapy. According to these studies, inhibition of FAS activity induces cell death in FAS-overexpressing cancer cell lines and prolongs survival of xenograft hosts. [3][4][5] In most reports on OA519/FAS overexpression published thus far, increased FAS expression was found only in a subset of cancers, 6 -12 questioning its role in the overall cancer process and limiting the applicability of anti-FAS therapy. In the first study of OA-519 expression in prostate cancer for instance, Shurbaji et al. 6 examined 42 paraffin-embedded prostate adenocarcinoma samples with an anti-OA-519/hrp antibody and found positive staining in 48% of the cancer samples. Little or no staining was observed in normal or hyperplastic prostate tissue. In a second study by this same group, 7 using an antibo...