Breast Cancer Research and Treatment

, Volume 169, Issue 1, pp 47–57 | Cite as

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

  • Virginie Ory
  • William B. Kietzman
  • Jacob Boeckelman
  • Bhaskar V. Kallakury
  • Anton Wellstein
  • Priscilla A. Furth
  • Anna T. Riegel
Preclinical study
  • 145 Downloads

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.

Keywords

Efatutazone PPARγ DCIS Breast cancer 

Notes

Acknowledgements

The project described above was supported by RO1CA205632 (ATR), the Nina Hyde Center Breast Cancer Fund (ATR), T32 Training Grant in Tumor Biology CA009686 (William Kietzman), and P30CA051008 (PI: Weiner) from the National Cancer Institute for usage of the following shared resources: microscopy and imaging, tissue culture, flow cytometry, histopathology, and animal models. We thank Maria Idalia Cruz and Carlos Benitez for their technical assistance with the in vivo drug treatment. We thank Sahar Alothman and Alqassem Abuarqoub for their help with the image quantitation.

Compliance with ethical standards

Conflict of interest

The authors do not have a financial relationship with Daiichi Sankyo pharmaceutical company and declare that they have no conflict of interest.

Ethical standards

The experiments in this study comply with the current laws of the country in which they were performed. The data sets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplementary material

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Supplementary material 1 (DOC 31 kb)
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Supplementary material 2 (TIFF 17785 kb)
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Supplementary material 3 (TIFF 13518 kb)
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Supplementary material 4 (TIFF 18234 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OncologyGeorgetown UniversityWashingtonUSA
  2. 2.Department of PathologyGeorgetown UniversityWashingtonUSA
  3. 3.Department of MedicineGeorgetown UniversityWashingtonUSA
  4. 4.The Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA

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