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Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes

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Abstract

One of the active intracellular pathways/networks in triple-negative breast carcinoma (TNBC) is that of the androgen receptor (AR). In this study, we examined AR and androgen-metabolising enzyme immunoreactivity in subcategories of TNBC to further elucidate the roles of androgenic pathways in TNBC. We utilised formalin-fixed paraffin-embedded breast cancer samples from ductal carcinoma in situ (DCIS) and invasive ductal carcinoma patient cohorts. We then used immunohistochemistry to classify these samples into basal-like and non-basal samples and to assess interactions between AR, androgen-metabolising enzymes and proliferation. To further substantiate our hypothesis and provide mechanistic insights, we also looked at the expression and regulation of these factors in publically available microarray data and in a panel of TNBC AR-positive cell lines. DCIS was associated with higher levels of AR and enzymes (p < 0.02), although a similar difference was not noticed in basal and non-basal samples. AR and enzymes were correlated in all states. In TNBC cell lines (MDA-MD-453, MFM-223 and SUM185-PE), we found that DHT treatment up-regulated 5αR1 and 17βHSD5 suggesting a mechanistic explanation for the correlations observed in the histological samples. Publicly available microarray data in TNBC cases suggested similar patterns to those observed in histological samples. In the majority of settings, including publically available microarray data, an inverse association between AR and proliferation was detected. These findings suggest that decreases in AR and androgen-metabolising enzymes may be involved in the increased biological aggressiveness in TNBC development.

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Abbreviations

5αR1:

Five alpha reductase one

17βHSD5:

Seventeen beta hydroxysteroid dehydrogenase five

AR:

Androgen receptor

BL2:

Basal-like group two

CK5/6:

Cytokeratin five/six

DCIS:

Ductal carcinoma in situ

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial to mesenchymal transition

ER:

Oestrogen receptor

FOXA1:

Forkhead box protein A1

IDC:

Invasive ductal carcinoma

LAR:

Luminal androgen receptor

LI:

Labelling index

mRNA:

Messenger ribonucleic acid

MSL:

Mesenchymal stem like

PCNA:

Proliferating cell nuclear antigen

RPL13A:

Ribosomal protein L 13a

TNBC:

Triple-negative breast cancer

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Acknowledgments

This study was in part supported by a research grant from Astra-Zeneca Japan. We would also like to acknowledge the Department of Pathology, Ramathibodi Hospital, Thailand for their kindness in sharing their TNBC IDC samples with us and the support from the technical staff at Tohoku University hospital and Mr. S. Nakamura for his valuable contribution to immunostaining slides. In addition, we would like to acknowledge the contribution of Mr. R. Stodart in proofreading of the manuscript text. Keely M. McNamara was supported in this work by a JSPS-AAS postdoctoral fellowship. Kristy A. Brown is supported by a NHMRC (Australia) Career Development Award GNT1007714.

Conflict of interest

The authors declare that they have no competing or conflicting interests.

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Authors and Affiliations

  1. Department of Pathology, Tohoku University School of Medicine, Sendai, Japan

    Keely M. McNamara, Tomomi Yoda, Alif Meem Nurani, Yukiko Shibahara, Yasuhiro Miki, Yasuhiro Nakamura, Yang Yang, Eriko Abe, Takashi Suzuki, Noriko Nemoto, Minoru Miyashita, Kentaro Tamaki & Hironobu Sasano

  2. Department of Surgery, Tohoku University School of Medicine, Sendai, Japan

    Noriko Nemoto, Minoru Miyashita, Kentaro Tamaki, Takanori Ishida & Noriaki Ohuchi

  3. Department of Physiology, Harbin Medical University Daqing Branch, Daqing, China

    Lin Wang

  4. Department of Pathology, St. Lukes Hospital, Tokyo, Japan

    Koyu Suzuki, Yang Yang & Eriko Abe

  5. Department of Pathology, Tohoku Kosai Hospital, Sendai, Japan

    Hisashi Hirakawa

  6. Department of Breast Surgery, Nahanishi Clinic, Okinawa, Japan

    Kentaro Tamaki

  7. Metabolism and Cancer Laboratory, Prince Henry’s Institute, Melbourne, VIC, Australia

    Kristy A. Brown

Authors
  1. Keely M. McNamara
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  2. Tomomi Yoda
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  3. Alif Meem Nurani
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  4. Yukiko Shibahara
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  5. Yasuhiro Miki
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  6. Lin Wang
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  7. Yasuhiro Nakamura
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  8. Koyu Suzuki
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  9. Yang Yang
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  10. Eriko Abe
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  11. Hisashi Hirakawa
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  12. Takashi Suzuki
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  13. Noriko Nemoto
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  14. Minoru Miyashita
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  15. Kentaro Tamaki
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  16. Takanori Ishida
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  17. Kristy A. Brown
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  18. Noriaki Ohuchi
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  19. Hironobu Sasano
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Correspondence to Keely M. McNamara.

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McNamara, K.M., Yoda, T., Nurani, A.M. et al. Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes. Breast Cancer Res Treat 145, 281–293 (2014). https://doi.org/10.1007/s10549-014-2942-6

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  • DOI: https://doi.org/10.1007/s10549-014-2942-6

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