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Inhibition of Peroxisome Proliferator-Activated Receptor Increases Estrogen Receptor–Dependent Tumor Specification

¹ Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia and ² Chemoprevention Agent Development and Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Robert I. Glazer, Georgetown University, 3970 Reservoir Road, Northwest, Research Building, Room W318, Washington, DC 20007. Phone: 202-687-8324; Fax: 202-687-7505; E-mail: glazerr{at}georgetown.edu.

Key Words: PPAR • ERK • ER • mammary carcinogenesis • stem cells

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that regulates gene transcription associated with intermediary metabolism, adipocyte differentiation, and tumor suppression and proliferation. To understand the role of PPAR in tumorigenesis, transgenic mice were generated with mammary gland–directed expression of the dominant-negative transgene Pax8PPAR. Transgenic mice were phenotypically indistinguishable from wild-type (WT) mice, but mammary epithelial cells expressed a greater percentage of CD29^hi/CD24^neg, CK5⁺, and double-positive CK14/CK18 cells. These changes correlated with reduced PTEN and increased Ras and extracellular signal-regulated kinase (ERK) and AKT activation. Although spontaneous tumorigenesis did not occur, transgenic animals were highly susceptible to progestin/7,12-dimethylbenz(a)anthracene–induced mammary carcinogenesis, which in contrast to WT mice resulted in a high tumor multiplicity and, most importantly, in the appearance of predominantly estrogen receptor –positive (ER⁺) ductal adenocarcinomas. Tumors expressed a similar PTEN^lo/pERK^hi/pAKT^hi phenotype as mammary epithelium and exhibited high activation of estrogen response element–dependent reporter gene activity. Tumorigenesis in MMTV-Pax8PPAR mice was insensitive to the chemopreventive effect of a PPAR agonist but was profoundly inhibited by the ER antagonist fulvestrant. These results reveal important new insights into the previously unrecognized role of PPAR in the specification of mammary lineage and the development of ER⁺ tumors. [Cancer Res 2009;69(2):687–94]