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Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers

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Abstract

Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.

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Abbreviations

AIs:

Aromatase inhibitors

3β-diol:

5α-Androstane-3β, 17β-diol

A-diol:

Androst-5-ene-3β, 17β-diol

ER:

Estrogen receptor α

E2:

Estradiol

E1S:

Estrone sulfate

SRD5A1:

5α-Reductase type 1 mRNA

3β-HSD type 1:

3β-Hydroxysteroid dehydrogenase type 1 protein

HSD3B1:

3β-Hydroxysteroid dehydrogenase type 1 mRNA

STS:

Steroid sulfatase protein

STS:

Steroid sulfatase mRNA

17β-HSD type 1:

17β-Hydroxysteroid dehydrogenase type 1 protein

HSD17B1:

17β-Hydroxysteroid dehydrogenase type 1 mRNA

DHEAS:

Dehydroepiandrosterone sulfate

DHT:

Dihydrotestosterone

TS:

Testosterone

DHEA:

Dehydroepiandrosterone

IHC:

Immunohistochemical

FISH:

Fluorescence in situ hybridization

GFP:

Green fluorescent protein

Ds-Red:

Fluorescent protein from Discosoma

FFPE:

Formalin-fixed paraffin-embedded

E1:

Estrone

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Acknowledgments

The authors thank Yuko Seino for technical support, and Prof. Takashi Suzuki (Tohoku University Department of Pathology and Histotechnology) for discussions and helpful suggestions. This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan; a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan; the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO); and a grant from the Smoking Research Foundation.

Ethical standards

All experiments complied with the current laws of Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Molecular and Functional Dynamics Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Toru Hanamura, Toshifumi Niwa, Tatsuyuki Gohno & Shin-ichi Hayashi

  2. Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Nagano, Japan

    Toru Hanamura & Ken-ichi Ito

  3. Department of Pathology, Saitama Cancer Center, Saitama, Japan

    Masafumi Kurosumi

  4. Division of Breast Surgery, Saitama Cancer Center, Saitama, Japan

    Hiroyuki Takei

  5. Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan

    Yuri Yamaguchi

  6. Center for Regulatory Epigenome and Diseases, Graduate School of Medicine, Tohoku University, Sendai, Japan

    Shin-ichi Hayashi

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  1. Toru Hanamura
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  2. Toshifumi Niwa
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  3. Tatsuyuki Gohno
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  4. Masafumi Kurosumi
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  5. Hiroyuki Takei
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  7. Ken-ichi Ito
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Correspondence to Toru Hanamura.

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Hanamura, T., Niwa, T., Gohno, T. et al. Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers. Breast Cancer Res Treat 143, 69–80 (2014). https://doi.org/10.1007/s10549-013-2788-3

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