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01-05-2018 | Preclinical study

The PPARγ agonist efatutazone delays invasive progression and induces differentiation of ductal carcinoma in situ

Authors: Virginie Ory, William B. Kietzman, Jacob Boeckelman, Bhaskar V. Kallakury, Anton Wellstein, Priscilla A. Furth, Anna T. Riegel

Published in: Breast Cancer Research and Treatment | Issue 1/2018

Abstract

Purpose

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion of the breast considered a precursor of invasive ductal carcinoma. This study aimed to determine whether activated PPARγ acts as a tumor suppressor in human DCIS progression.

Methods

We utilized the high-affinity PPARγ agonist, efatutazone, to activate endogenous PPARγ in a well-defined model for the progression of basal (triple negative) DCIS, MCFDCIS cells, cultured under 2D and 3D conditions. We studied the effects of activated PPARγ on DCIS progression in MCFDCIS xenograft and C3(1)/Tag transgenic mice treated with 30 mg/kg of efatutazone.

Results

In vitro, efatutazone did not alter the MCFDCIS cell proliferation but induced phenotypic and gene expression changes, indicating that activated PPARγ is able to differentiate MCFDCIS cells into more luminal and lactational-like cells. In addition, MCFDCIS tumorsphere formation in 3D was reduced by PPARγ activation. In vivo, efatutazone-treated MCFDCIS tumors exhibited fat deposition along with upregulation of PPARγ responsive genes in both epithelial and stromal compartments, suggesting features of milk-producing mammary epithelial cell differentiation. The efatutazone-treated lesions were less invasive with fewer CD44+/p63+ basal progenitor cells. PPARγ activation downregulated Akt phosphorylation in these tumors, although the ERK pathway remained unchanged. Similar trends in gene expression changes consistent with lactational and luminal cell differentiation were observed in the C3(1)/Tag mouse model after efatutazone treatment.

Conclusions

Our data suggest that activation of the PPARγ pathway differentiates DCIS lesions and may be a useful approach to delay DCIS progression.

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Title: The PPARγ agonist efatutazone delays invasive progression and induces differentiation of ductal carcinoma in situ
Authors: Virginie Ory
William B. Kietzman
Jacob Boeckelman
Bhaskar V. Kallakury
Anton Wellstein
Priscilla A. Furth
Anna T. Riegel
Publication date: 01-05-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4649-y

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