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

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