Cancer Therapy Vol 3, page 545 Unlike other 17HSDs, which belong to the shortchain dehydrogenase/reductase superfamily, 17HSD type 5, a reductive 17HSD, is a member of the aldo-keto reductase superfamily (Dufort et al, 1999; Luu-The et al, 2001). 17HSD5 has a broad tissue distribution and it recognizes several different substrates in in vitro assays (Luu-The et al, 2001; Penning et al, 2001). 17HSD5 has some activity as a reductase of 3-keto and 17-keto and as an oxidase of 3"- and 17!-hydroxysteroids (Penning et al, 2001). Human 17HSD5 also has a high level of 20"hydroxysteroid dehydrogenase activity, which inactivates progesterone to 20"-OH-progesterone (Luu-The et al, 2001). In myeloid leukemia cell lines, this enzyme possesses marked 11-ketoreductase activity, converting prostaglandin D2 to PGF2" and functions to regulate cell differentiation (Desmond et al, 2003). So far, little is known about the role of 17HSD5 in breast tissue, but it may be involved in the metabolism of female sex steroids. In the prostate, 17HSD5 catalyzes the formation of testosterone and the inactivation of DHT (Dufort et al, 1999). Human 17HSD type 7 is a membrane-associated reductive enzyme converting estrone to estradiol and DHT to an estrogenic metabolite, 5"-androstane-3!, 17!-diol, thereby catalyzing the reduction of the keto group in either the 17- or the 3-position of the substrate. Minor 3!-HSDlike activity towards progesterone and 20"hydroxyprogesterone, leading to inactivation of progesterone by 17HSD type 7, has also been detected (Tรถrn et al, 2003). Human 17HSD type 7 is expressed in steroidogenic cells and several peripheral tissues, such as liver, lung and thymus. Its function is not known, but it may be responsible for the local production of estrogenic metabolites in peripheral tissue (Tรถrn et al, 2003). 17HSD type 7 has also other substrates apart from sex steroids (Breitling et al, 2001). It was shown that the enzyme acts as a 3-ketosteroid reductase in cholesterol biosynthesis, converting zymosterone to zymosterol (Marijanovic et al, 2003).
etiology (Vihko and Apter 1989). Premature loss of ovarian function greatly reduces the breast cancer risk, supporting the idea that ovarian hormones are important factors in breast carcinogenesis. While the exact mechanisms of estrogen action in breast cancer development remain to be elucidated, it has been shown that estrogens induce and promote mammary cancer in rodents (Nandi et al, 1995) and exert proliferative effects on cultured human breast cancer cells (Cullen and Lippman 1989). A positive correlation between the plasma estrogen concentration and the breast cancer risk has been observed in postmenopausal women (Tonilo et al, 1995; Berrino et al, 1996; Hankinson et al, 1998). The majority of breast cancers, however, are detected during the postmenopausal period, when the ovaries have ceased to produce estrogens. Despite the low circulating estrogen concentrations in these patients, the tissue concentrations of estrogens in the breast are higher and, further, the estradiol concentration has been shown to be significantly higher in breast tumors than in normal breast tissue (Vermeulen et al, 1986; Pasqualini and Chetrite 2002). The proliferation of breast epithelial cells is maximal during the second half of the menstrual cycle, at the time when both estradiol and progesterone are secreted (Anderson et al, 1982) suggesting that also progesterone may have a role in the development of breast cancer. Both 17HSD type 1 and type 2 are expressed in the epithelium of normal breast tissue in premenopausal women (Miettinen et al, 1999) and oxidative activity seems to be the dominant form in non-tumorous cells (Miettinen et al, 1999, Spiers et al, 1998). The type 1 enzyme is expressed in the epithelial cells of ducts and alveoli throughout the menstrual cycle. Breast cancer cell lines have been shown to express 17HSD type 1, 17HSD type 2, or both enzymes (Miettinen et al, 1996b). We recently analyzed the mRNA expressions of the 17HSD type 1, type 2 and type 5 enzymes were analyzed in 794 breast carcinoma specimens by using tissue microarrays and normal histological sections. The results were correlated with ER" and ER !, progesterone receptor (PR), Ki67 and c-erbB-2 expressions analyzed by immunohistochemical techniques and the the TumorNode-Metastasis (TNM) classification, tumor grade, disease-free interval and survival of the patients (Oduwole et al, 2004). Both 17HSD type 1 and type 2 mRNAs were detected in the normal breast tissue of premenopausal women, but no expression of 17HSD type 1 or 17HSD type 2 mRNA was observed in the normal tissue specimens from postmenopausal women. The mRNAs were localized in the ductal or lobular epithelial cells (Oduwole et al, 2004). In malignant breast lesions, variable expression patterns for 17HSD type 1 and type 2 mRNA were observed (Figure 2). There were 16 % 17HSD type 1 mRNA and 25 % type 2 mRNA positive cases. No significant differences were observed for the 17HSD type 1 enzyme in malignant tissue between the pre- and postmenopausal groups. In contrast, the number of cases showing signals for 17HSD type 2 mRNA was higher in the premenopausal than the postmenopausal patients.
III. 17HSDs in breast cancer Estrogens are essential for the growth and differentiation of the mammary gland. The female mammary gland undergoes a surge of cell divisions during puberty. There is also cyclic proliferation and involution in the breast during the menstrual cycle throughout adult life (Russo et al, 1999). Multiplication of normal breast cells cultured in vitro is increased by the addition of estradiol to the culture (Mauvais-Jarvis et al, 1986). Further, the phenotypes of estrogen receptor " (ER") and ! (ER!) knockout mice indicate that ER" is important for the growth and development of the mammary gland, whereas ER! is involved in the terminal differentiation of glandular epithelium (Couse and Korach 1999; Foster et al, 2002). Breast cancer is the most common malignant neoplastic disease in the female. The majority of breast carcinomas are invasive ductal or lobular carcinomas. Several endocrine and reproductive factors, such as early age at menarche, nulliparity, or delayed first childbirth, late age at menopause and obesity, are associated with its
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