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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...

Monotherapy with 150 mg. bicalutamide is an attractive alternative to castration in patients with locally advanced prostate cancer for whom immediate hormone therapy is indicated.

A substantial subset of breast, colorectal, ovarian, endometrial and prostatic cancers displays markedly elevated expression of immunohistochemically detectable fatty acid synthase, a feature that has been associated with poor prognosis and that may be exploited in anti‐neoplastic therapy. Here, using an RNA array hybridisation technique complemented by in situ hybridisation, we report that in prostate cancer fatty acid synthase expression is up‐regulated at the mRNA level together with other enzymes of the same metabolic pathway. Contrary to the observations that in many cell systems (including androgen‐stimulated LNCaP prostate cancer cells) fatty acid and cholesterol metabolism are co‐ordinately regulated so as to supply balanced amounts of lipids for membrane biosynthesis, storage or secretion, no changes in the expression of genes involved in cholesterol synthesis were found. These findings point to selective activation of the fatty acid synthesis pathway and suggest a shift in the balance of lipogenic gene expression in a subgroup of prostate cancers. Int. J. Cancer 88:176–179, 2000. © 2000 Wiley‐Liss, Inc.

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