Endogenous aromatization of testosterone results in growth stimulation of the human MCF-7 breast cancer cell line

Sonne-Hansen, Katrine; Lykkesfeldt, Annè E.

doi:10.1016/j.jsbmb.2004.11.005

Cited by 73 publications

(59 citation statements)

References 53 publications

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“…Spinola et al (1988) previously showed that treatment with an aromatase inhibitor (4-hydroxyandrostenedione) markedly elevated intratumoral testosterone concentrations in dimethylbenz(a)anthracene-induced rat mammary tumors. In addition, Sonne-Hansen & Lykkesfeldt (2005) reported that aromatase preferred testosterone as a substrate in MCF-7 cells. Very recently, Suzuki et al (2007) demonstrated that aromatase expression was inversely associated with intratumoral DHT concentrations in IDC and aromatase inhibitors suppressed the DHT synthesis from androstenedione in coculture experiments.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Shibuya¹,

Suzuki²,

Miki³

et al. 2008

Endocrine Related Cancer

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It is well known that sex steroids play important roles in the development of invasive ductal carcinoma (IDC) of the human breast. However, biological significance of sex steroids remains largely unclear in ductal carcinoma in situ (DCIS), regarded as a precursor lesion of IDC, which is partly due to the fact that the intratumoral concentration of sex steroids has not been examined in DCIS. Therefore, in this study, we first examined the intratumoral concentrations of estradiol and 5a-dihydrotestosterone (DHT) using liquid chromatography/electrospray tandem mass spectrometry in DCIS. Intratumoral concentrations of both estradiol and DHT were threefold higher in DCIS than non-neoplastic breast tissues and estrogen-producing enzymes (aromatase, steroid sulfatase, and 17b-hydroxysteroid dehydrogenase type 1 (17bHSD1)), and androgen-producing enzymes (17bHSD5 and 5a-reductase type 1 (5aRed1)) were abundantly expressed in DCIS by real-time PCR and immunohistochemical analyses. The intratumoral concentration of DHT was significantly lower in IDC than DCIS, while the expression of aromatase mRNA in carcinoma cells and intratumoral stromal cells was significantly higher in IDC than those in DCIS. Immunohistochemistry for sex steroid-producing enzymes in DCIS demonstrated that 5aRed1 immunoreactivity was positively correlated with Ki-67 labeling index and histological grade and was also associated with an increased risk of recurrence in patients with DCIS examined. Results of our study suggest that intratumoral concentrations of estradiol and DHT are increased in DCIS, which is possibly due to intratumoral production of these steroids. Therefore, estradiol and DHT may play important roles in the development of DCIS of the human breast.

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Section: Discussionmentioning

confidence: 99%

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Shibuya¹,

Suzuki²,

Miki³

et al. 2008

Endocrine Related Cancer

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“…A considerable amount of work has been done over the years studying the effects of androgens on the proliferation of breast cancer cells [1,[7][8][9][10][11][12]. The literature is, however, somewhat confusing, with conflicting data coming from relatively similar experimental systems.…”

Section: Discussionmentioning

confidence: 99%

“…We were therefore interested in the possibility that androgens and/or their downstream metabolites might play a role in resistance to AI therapy. A number of studies of the effects of androgens on breast cancer cells have been published, with the majority focusing on the effects of testosterone (TS) and 5α-dihydrotestosterone (DHT) on breast cancer growth [1,[7][8][9][10][11][12]. Little is known, however, about the effects of these compounds on breast cancer cell growth under conditions of profound estrogen deprivation, similar to conditions found in women treated with AIs.…”

Section: Introductionmentioning

confidence: 99%

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Sikora

Cordero

Larios

et al. 2008

Breast Cancer Res Treat

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The aromatase inhibitors (AIs) are used to treat estrogen receptor-positive (ER+) breast tumors in post-menopausal women, and function by blocking the conversion of adrenal androgens to estrogens by the enzyme CYP19 aromatase. Breast cancer patients receiving AI therapy have circulating estrogen levels below the level of detection; however, androgen concentrations remain unchanged. We were interested in studying the effects of androgens on breast cancer cell proliferation under profound estrogen-deprived conditions. Using in vitro models of estrogen-dependent breast cancer cell growth we show that the androgens testosterone and 5α-dihydrotestosterone induce the growth of MCF-7, T47D and BT-474 cells in the absence of estrogen. Furthermore, we demonstrate that under profound estrogen-deprived conditions these breast cancer cells up-regulate steroidogenic enzymes that can metabolize androgens to estrogens. Lastly, we found that the downstream metabolite of 5α-dihydrotestosterone, 5α-androstane-3β,17β-diol (3βAdiol), is estrogenic in breast cancer cells, and induces growth and ER-signaling via activation of ERα. In conclusion, our results show that breast cancer cells deprived of estrogen up-regulate steroidogenic enzymes and metabolize androgens to estrogen-like steroids. The generation of estrogen-like steroids represents a potential mechanism of resistance to aromatase inhibitors.

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“…Although the aromatisation of androgens in breast cancer cells has remained controversial, low, but reproducible aromatase activity has been detected in MCF-7 cells (Sonne-Hansen & Lykkesfeldt 2005). To avoid oestrogen formation, several aromatase inhibitors have been widely used in therapeutic schemes in breast cancer (Coombes et al 1987, Santen et al 1990, Demers 1994, Goss 1999, Ragaz 1999, Sasano et al 1999, although the oestrogen-like effects of androgens are not completely suppressed by this treatment (Brodie et al 1977, Brodie & Longcope 1980, Coombes et al 1984, Wing et al 1985, Lippman 1998, Buzdar 2002, Lønning 2004, Brueggemeier et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern

Pérez‐Palacios

Santillán

Garcı́a-Becerra

et al. 2006

Journal of Endocrinology

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Breast cancer is a sex steroid hormone-dependent malignant neoplasia. The role of oestradiol in this malignancy has been well documented; however, the involvement of androgens has remained controversial. To determine the role of nonphenolic androgen metabolites in human breast cancer, we studied the metabolism of [ C] testosterone and [14 C] androstenedione in oestrogen-dependent MCF-7 cells and non-oestrogen-dependent MDA-MB 231 cells, at different substrate concentrations (1-10 mM) and time periods (30 min-48 h). Cultured non-oestrogen-dependent HeLa and yeast cells served as controls. Metabolites were identified and quantified by reverse isotope dilution. A distinctive pattern of androgen metabolism was identified in MCF-7 cells, being the 5a-androstane-3a,17b-diol (3a,5a-diol) and its 3b epimer (3b,5a-diol), the major conversion products of testosterone (48$3%), with 5a-dihydrotestosterone as intermediary. The formation of 3a,5a-diol and 3b,5a-diol (diols) was substrate concentration-and time-dependent, and abolished by finasteride. In contrast, very little of any diol formation was observed in MDA-MB 231, HeLa and yeast cell incubations. Additional enzyme gene expression studies revealed an overexpression of 5a-steroid reductase type-1 in MCF-7 cells, as compared with MDA-MB 231 cells. The oestrogen-like activities of diols were assessed in HeLa cells co-transfected with expression vectors for a or b subtypes of the human oestrogen receptor (hER) genes and for an oestrogen-responsive reporter gene. The results show that 3b, 5a-diol and to a lesser extent 3a,5a-diol bind with high relative affinity to hERa and hERb.Both diols induced hER-mediated reporter gene transactivation in a dose-response manner, similar to that induced by oestradiol, though with lower potency, an effect that was abolished by ICI-182 780. Furthermore, 3b,5a-diol and to lesser extent 3a,5a-diol induced MCF-7 cell proliferation. The overall results demonstrated that MCF-7 cells exhibit enhanced expression and activity of androgen-metabolising enzymes, leading to rapid and large diol formation, and provide evidence that these androgen metabolites exert a potent oestrogen-agonistic effect, at genomic level, in oestrogen-dependent breast cancer cells. The data suggest that diols may act as in situ intracrine factors in breast cancer and that its formation can be pharmacologically inhibited.

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Endogenous aromatization of testosterone results in growth stimulation of the human MCF-7 breast cancer cell line

Cited by 73 publications

References 53 publications

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

Enhanced formation of non-phenolic androgen metabolites with intrinsic oestrogen-like gene transactivation potency in human breast cancer cells: a distinctive metabolic pattern

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