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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research Article

Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells

Authors: Derek F. Amanatullah, John S. Tamaresis, Pauline Chu, Michael H. Bachmann, Nhat M. Hoang, Deborah Collyar, Aaron T. Mayer, Robert B. West, William J. Maloney, Christopher H. Contag, Bonnie L. King

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear.

Methods

Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular  bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry.

Results

ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation.

Conclusions

These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance.
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Metadata
Title
Local estrogen axis in the human bone microenvironment regulates estrogen receptor-positive breast cancer cells
Authors
Derek F. Amanatullah
John S. Tamaresis
Pauline Chu
Michael H. Bachmann
Nhat M. Hoang
Deborah Collyar
Aaron T. Mayer
Robert B. West
William J. Maloney
Christopher H. Contag
Bonnie L. King
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0910-x

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