The PPAR[gamma] agonist efatutazone delays invasive progression and induces differentiation of ductal carcinoma in situ

• Published in: Breast cancer research and treatment Vol. 169; no. 1; p. 47
• Main Authors: Ory, Virginie, Kietzman, William B, Boeckelman, Jacob, Kallakury, Bhaskar V, Wellstein, Anton, Furth, Priscilla A, Riegel, Anna T
• Format: Journal Article
• Language: English
• Published: Springer 01.05.2018
• Subjects: Cell differentiation; Development and progression; Ductal carcinoma in situ; Gene expression; Genetic engineering; Invasive ductal carcinoma (Breast cancer)
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4649-y

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 PPAR[gamma] acts as a tumor suppressor in human DCIS progression. Methods We utilized the high-affinity PPAR[gamma] agonist, efatutazone, to activate endogenous PPAR[gamma] 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 PPAR[gamma] 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 PPAR[gamma] is able to differentiate MCFDCIS cells into more luminal and lactational-like cells. In addition, MCFDCIS tumorsphere formation in 3D was reduced by PPAR[gamma] activation. In vivo, efatutazone-treated MCFDCIS tumors exhibited fat deposition along with upregulation of PPAR[gamma] 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. PPAR[gamma] 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 PPAR[gamma] pathway differentiates DCIS lesions and may be a useful approach to delay DCIS progression.