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Development of complex model systems for analysis of cell‐cell and cell‐microenvironment interactions in breast cancer
Author(s) -
Andersen Anne Poder,
Ronnov-Jessen Lone,
Hulikova Alzbeta,
Swietach Pawel,
Pedersen Stine Falsig
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1064.1
Subject(s) - tumor microenvironment , downregulation and upregulation , protein kinase b , cancer research , cancer cell , microbiology and biotechnology , motility , chemistry , cell culture , pi3k/akt/mtor pathway , cell growth , phosphorylation , cancer , biology , signal transduction , biochemistry , tumor cells , genetics , gene
To study cancer development it is essential to employ models that recapitulate the tumor microenvironment. We previously showed that the Na + /H + exchanger NHE1 and the Na + , HCO 3 − cotransporter NBCn1 are essential for pH regulation in MCF‐7 breast cancer cells and their activity increased by ΔNErbB2 expression. Furthermore, NHE1 inhibition strongly sensitized ΔNErbB2‐ expressing MCF‐7 cells to chemotherapy‐induced death. Here, we explore the impact of specific aspects of the tumor microenvironment on pH‐regulatory and survival/motility signaling programs. Simulation of the tumor microenvironment (pH e 6.5, 1% O 2 , 7.5 mM lactate) elicited marked upregulation of Akt activity (Akt S473 phosphorylation) in MCF‐7 cells ± ΔNErbB2. In 2D co‐culture with primary human breast fibroblasts, MCF‐7 cells appeared to upregulate the lactate‐H + cotransporter MCT1 and EMT markers such as α‐smooth muscle actin. Finally, in MCF‐7 spheroids (3D multicellular growths), the expression patterns of NHE1, NBCn1 and pAkt/Akt were altered compared to 2D mono‐culture controls. In conclusion, the tumor microenvironment profoundly impacts on pH regulatory ion transport proteins and survival signaling in breast cancer cell models. Funding: Novo Foundation.