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

Open Access 01-12-2017 | Research article

Pathomimetic avatars reveal divergent roles of microenvironment in invasive transition of ductal carcinoma in situ

Authors: Mansoureh Sameni, Dora Cavallo-Medved, Omar E. Franco, Anita Chalasani, Kyungmin Ji, Neha Aggarwal, Arulselvi Anbalagan, Xuequn Chen, Raymond R. Mattingly, Simon W. Hayward, Bonnie F. Sloane

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

The breast tumor microenvironment regulates progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). However, it is unclear how interactions between breast epithelial and stromal cells can drive this progression and whether there are reliable microenvironmental biomarkers to predict transition of DCIS to IDC.

Methods

We used xenograft mouse models and a 3D pathomimetic model termed mammary architecture and microenvironment engineering (MAME) to study the interplay between human breast myoepithelial cells (MEPs) and cancer-associated fibroblasts (CAFs) on DCIS progression.

Results

Our results show that MEPs suppress tumor formation by DCIS cells in vivo even in the presence of CAFs. In the in vitro MAME model, MEPs reduce the size of 3D DCIS structures and their degradation of extracellular matrix. We further show that the tumor-suppressive effects of MEPs on DCIS are linked to inhibition of urokinase plasminogen activator (uPA)/urokinase plasminogen activator receptor (uPAR)-mediated proteolysis by plasminogen activator inhibitor 1 (PAI-1) and that they can lessen the tumor-promoting effects of CAFs by attenuating interleukin 6 (IL-6) signaling pathways.

Conclusions

Our studies using MAME are, to our knowledge, the first to demonstrate a divergent interplay between MEPs and CAFs within the DCIS tumor microenvironment. We show that the tumor-suppressive actions of MEPs are mediated by PAI-1, uPA and its receptor, uPAR, and are sustained even in the presence of the CAFs, which themselves enhance DCIS tumorigenesis via IL-6 signaling. Identifying tumor microenvironmental regulators of DCIS progression will be critical for defining a robust and predictive molecular signature for clinical use.
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Metadata
Title
Pathomimetic avatars reveal divergent roles of microenvironment in invasive transition of ductal carcinoma in situ
Authors
Mansoureh Sameni
Dora Cavallo-Medved
Omar E. Franco
Anita Chalasani
Kyungmin Ji
Neha Aggarwal
Arulselvi Anbalagan
Xuequn Chen
Raymond R. Mattingly
Simon W. Hayward
Bonnie F. Sloane
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/s13058-017-0847-0

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