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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

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Abstract

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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Abbreviations

ER:

Estrogen receptor

3βAdiol:

5α-androstane-3β,17β-diol

AI:

Aromatase inhibitor

E2:

17β-estradiol

TS:

Testosterone

DHT:

5α-dihydrotestosterone

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Acknowledgements

This work was supported in part by the Breast Cancer Research Foundation grant N003173 and by U-01 GM61373 and T-32 GM007767 from the National Institute of General Medical Sciences, Bethesda, MD.

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Authors and Affiliations

  1. Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Matthew J. Sikora & James M. Rae

  2. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA

    Kevin E. Cordero, Jose M. Larios, Marc E. Lippman & James M. Rae

  3. Lombardi Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Michael D. Johnson

  4. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, 4520B MSRB1, Ann Arbor, MI, 48109-0612, USA

    James M. Rae

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  1. Matthew J. Sikora
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Correspondence to James M. Rae.

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Sikora, M.J., Cordero, K.E., Larios, J.M. et al. The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance. Breast Cancer Res Treat 115, 289–296 (2009). https://doi.org/10.1007/s10549-008-0080-8

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