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The presence and impact of estrogen metabolism on the biology of triple-negative breast cancer

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Abstract

Purpose

While triple-negative breast cancer (TNBC) is negative for estrogen receptor alpha, a substantial proportion of carcinomas express estrogen receptor beta (ERβ); consequently, estrogen actions and metabolism may be relevant in this cancer subtype.

Methods

A cohort of 81 TNBC patients from Tohoku University Hospital, Japan were characterised with regard to the expression of estrogen receptor beta and enzymes known to modulate levels of estrogens in breast and other tissues (Aromatase, 17-beta- Hydroxysteroid dehydrogenases 1, 2 and 6). This was done at the protein level by means of immunohistochemistry. As this cohort has been previously characterised for androgens, this also allows for comparison between the expressions of estrogen-related proteins and of androgen-related proteins. Preliminary mechanistic studies in cell culture were also undertaken.

Results

17βHSD2 was detected in the highest number of cases followed by 17βHSD1, 17βHSD6 and aromatase. When comparing the expression of ERβ with that of the enzymes, it was positively correlated with the expression of 17βHSD6 (p < 0.05) and trended towards correlation with dual expression of 17βHSD1 and 2 (p < 0.07). 17βHSD1 was associated with significantly reduced tumour volume (p = 0.0025), while ERβ was associated with a trend towards reduced lymphovascular invasion, (p < 0.061). Interestingly, in survival analysis, 17βHSD6 expression was the only one of these five factors that influenced survival, with positive samples being associated with longer disease-free survival compared to those that were negative for 17βHSD6 (p < 0.05). In assessing associations with expression of proteins in the androgenic pathway, expression of aromatase appeared to be associated with androgenic pathways in TNBC patients (p < 0.05). Due to this association and the potential relevance to androgen-directed therapies in TNBC, we evaluated this interaction in vitro. We observed androgen-dependent upregulation of aromatase and ERβ in a subset of AR expressing TNBC cell lines (MDA-MB-453, SUM-185-PE and MFM-223).

Conclusion

Overall this study suggests the presence of, and a potential protective effect of estrogens in TNBC.

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Acknowledgements

The authors would like to acknowledge all the members of their laboratories, whose informal input was extremely valuable. The authors would like to acknowledge the extremely capable assistance provided by both Katsuhiko Ono and Yoshiaki Onodera, in particular, and more generally by the staff at the Anatomical Pathology department of the Tohoku University.

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Authors and Affiliations

  1. Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Keely May McNamara, Saki Oguro, Fumiya Omata, Kyoko Kikuchi, Fouzia Guestini, Ishida Takanori, Noriaki Ohuchi & Hironobu Sasano

  2. Departments of Pathology and Surgery, St Lukes Hospital, Tokyo, Japan

    Koyu Suzuki, Yang Yang & Eriko Abe

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

    Hisashi Hirakawa

  4. Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia

    Kristy A. Brown

Authors
  1. Keely May McNamara
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  2. Saki Oguro
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  3. Fumiya Omata
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Correspondence to Keely May McNamara.

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Supplementary material 1 (JPEG 60 kb)

10549_2016_4050_MOESM2_ESM.pdf

Supplementary material 2 (PDF 307 kb) Figure S1 Potential pathways of estrogen metabolism in TNBC. These figures show the enzymatic conversion of steroids (black lines) alongside the predominant or only enzymes known to catalyse that reaction (white box on top of black line). In addition, steroids as potential ligands of receptors are shown(grey dotted lines). While we and others have previously studied androgen metabolism pathways in detail (5αR1, 17βHSD5) estrogen metabolism pathways have been relatively neglected, even though these are only one enzymatic step from androgens. The presence of ERβ in TNBC tissue provides an important rationale for studying these enzymes. It should also be noted as in the arrows at the right that the presence or absence of these enzymes can determine if a carcinoma is androgen dominant or estrogen dominant. Estrogen metabolism will reduce the pool of circulating androgens and likewise androgen metabolism will limit the pool of circulating estrogens, thus these two pathways interact on multiple levels. Two pathways of estrogen metabolism are shown. In red, the canonical pathway of estrogen synthesis is given involving the non-reversible aromatization of C19 steroids to C18 steroids with the use of relatively low-potency androgens as estrogenic precursors. In blue the 3β-diol pathway is highlighted with the use of the most-potent androgen, DHT as a precursor to the production of an ERβ-selective C19 steroid, 3β-diol

10549_2016_4050_MOESM3_ESM.pdf

Supplementary material 3 (PDF 455 kb) Figure S2 Changes in expression between Normal, DCIS and IDC. IHC of histologically normal adjacent to the DCIS shown here is given in A–D. IHC immunoreactivity of ERβ1, aromatase and 17βHSD6 in DCIS is shown (E–H). Based on changes observed between normal and cancerous and DCIS and IDC components we examined the changes in expression of ERβ (I), aromatase (J) and 17βHSD6 (K) between TNBC DCIS and the levels observed in the IDC samples. In this analysis, we noted a significant decrease in the expression of 17βHSD6 (p < 0.001, Chi squared Pearsons) with no other significant changes observed on the basis of histology. The scale bar represents 200 μM

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McNamara, K.M., Oguro, S., Omata, F. et al. The presence and impact of estrogen metabolism on the biology of triple-negative breast cancer. Breast Cancer Res Treat 161, 213–227 (2017). https://doi.org/10.1007/s10549-016-4050-2

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