Androgens influence estrogen-induced responses in human breast carcinoma cells through cytochrome P450 aromatase

Burak, William E.; Quinn, Anne L.; Farrar, William B.; Brueggemeier, Robert W.

doi:10.1023/a:1005782311558

Cited by 38 publications

(48 citation statements)

References 21 publications

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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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Although the aromatase gene was found to be amplified in MCF-7 cells, as shown by Southern and DNA slot blot analyses Kitawaki et al (1992) reported that, by converting androgen to estrogen, the endogenous aromatase enzyme in the MCF-7 breast cancer cells (ER-positive cells) could stimulate DNA synthesis, and the stimulation was abolished by the administration of aromatase inhibitors. Burak et al (1997) demonstrated that androgen elicited an estrogen-induced response in MCF-7 cells through aromatase. These results indicate that aromatase, at a level as found in MCF-7 cells, is capable of generating sufficient estrogen to evoke an estrogen-dependent response.…”

Section: Consequence Of Aromatase Expression In Breast Tumorsmentioning

confidence: 99%

Breast tumor aromatase: functional role and transcriptional regulation.

Chen¹,

Zhou²,

Okubo³

et al. 1999

Endocrine-Related Cancer

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Aromatase has been shown to be expressed at a higher level in human breast cancer tissue than in normal breast tissue, by means of enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture including MCF-7 breast cancer cells, animal experiments using aromatasetransfected breast cancer cells, and transgenic mouse studies have demonstrated that estrogen production in situ plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase is believed to be able to stimulate breast cancer growth through both autocrine and paracrine pathways, as demonstrated by a three-dimensional cell culture study. RT-PCR and gene transcriptional studies have revealed that the aromatase promoter is switched from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancerous tissue. Recently, we identified and characterized a cAMP-responsive element (CREaro) upstream from promoter I.3 by DNA deletion and mutational analyses. Our results from promoter functional analysis also demonstrated an interaction between the CREaro and the silencer element (S1) that was identified previously in our laboratory. In the presence of cAMP, the positive regulatory CREaro can overcome the action of the silencer on the function of promoter I.3. On the basis of results generated from our own and other laboratories, we propose that, in normal breast adipose stromal cells and fibroblasts, aromatase expression is driven by promoter I.4 (glucocorticoid dependent), and that the action of promoters I.3 and II is suppressed by the silencer negative regulatory element. However, in cancer cells and surrounding adipose stromal cells, the cAMP level increases, and aromatase promoters are switched to cAMP-dependent promoters -I.3 and II. Furthermore, we applied the yeast one-hybrid screening method to search for proteins interacting with the silencer element, S1. The major protein identified was ERRα-1; however, SF-1, which is present in the ovary, is not detected in breast cancer tissue. Using a reporter plasmid with the aromatase genomic fragment containing promoter I.3 and S1, in breast cancer SK-BR-3 cells, ERRα-1 was found to have a positive regulatory function. It is believed that the silencer element in the human aromatase gene may function Endocrine-Related Cancer (1999) 6 149-156 differently in different tissues, as a result of distinct expression patterns of transcription factors.

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“…In postmenopausal women, local aromatization of androgens to estrogens is the main source of estradiol in the tumor and surrounding tissue (Pike et al, 1993;Simpson et al, 1994). These local conversions of estrogens as well as the rate-limiting step of conversion of androstenedione to estrone are catalyzed by the aromatase cytochrome P450 complex (Means et al, 1989;Burak et al, 1997). Clinical ®ndings in patients with aromatase de®ciency as well as in a knockout mouse (ArKo) lacking functional aromatase, illustrate the role of this enzyme for the development of reproductive organs and mammary glands in female and for the regulation of gonadotropins in both male and female (Harada et al, 1992;Fisher et al, 1998).…”

Section: Introductionmentioning

confidence: 99%