The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

BMC Medicine

Research Article

Mariam Quinones¹  Timothy D Veenstra²  Zhen Xiao²  Xia Xu²  Barbara K Vonderhaar³  Erika Ginsburg³  Jodie M Fleming³  Tyler C Miller³  Matthew J Meyer³ 

[1] Bioinformatics and Computational Biosciences Branch, The Office of Science Management and Operations, National Institute of Allergy and Infectious Disease, Bethesda, MD, USA;Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, NCI-Frederick, Frederick, MD, USA;Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA;

关键词: Estrogen Receptor;    Breast Cancer Cell;    Progesterone Receptor;    Breast Tissue;    Estriol;   

DOI  :  10.1186/1741-7015-8-27

 received in 2010-05-05, accepted in 2010-05-21,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundBreast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from premenopausal African-American (AA) or Caucasian-American (CAU) breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo. We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women.MethodsThe effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested in vitro via soft agar and invasion assays, and in vivo via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry.ResultsMouse mammary glands humanized with premenopausal CAU fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA humanized glands. Examination of 164 ECM molecules and cytokines from CAU-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast ECM was isolated; invasion and soft agar assays demonstrated that estrogen receptor (ER)-, progesterone receptor (PR)/PR- cells were significantly more aggressive when in contact with AA ECM, as were ER+/PR+ cells with CAU ECM. Using zymography, protease activity was comparatively upregulated in CAU ECM. In xenograft models, CAU ECM significantly increased the tumorigenicity of ER+/PR+ cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed that only 1,759 of approximately 8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CAU unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CAU breast tissue.ConclusionsThis study details normal premenopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities.

【 授权许可】

Unknown   
© Fleming et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.