Increased expression of the Hedgehog (Hh) signaling pathway effector GLI1 in breast cancer patients has been shown to correlate inversely with disease free and overall survival. Activation of the Hh signaling pathway is known to promote proliferation of breast cancer cells and stimulate mammosphere formation. In addition, the Hh signaling pathway has been reported activated in CD44 positive breast cancer stem cells. Despite the evidence supporting a role for Hh signaling in breast cancer development and maintenance, the model systems to study the Hh pathway in breast carcinogenesis are limited.

We used a transgenic mouse model to show that GLI1 expression in the mammary gland cause tumor formation. The GLI1 induced primary tumors showed different histological characteristics, suggesting that the GLI1 expression influenced the tumor initiating cells. The GLI1 induced primary tumors were orthotopically transplanted on NOD/SCID mice and we have established serial transplantable tumor lines. The different histological characteristics of the individual primary tumors have been maintained for >10 serial transplantations in NOD/SCID mice. The stem cell marker CD44 is expressed in the mouse mammary gland ducts. The CD44 positive cell population is increased in the GLI1 induced tumors. The G protein coupled receptor (GPCR) like protein Lgr5 has been suggested as a stem cell marker in several tissues, including mammary gland. We show that cells in the basal layer of the adult mammary gland ducts express Lgr5. The Lgr5 positive cell population is increased in the GLI1 induced tumors, suggesting a basal like characteristic of these tumors.

Taken together, our data show that expression of GLI1 in the mammary gland result in formation of mammary gland tumors with heterogeneous histological characteristics. The cell populations identified by the stem cell markers CD44 or Lgr5 are increased in the GLI1 induced tumors compared with the normal mammary gland. Furthermore, we have established serial transplantable GLI1 induced mammary gland tumor lines. These serial transplantable tumor lines are novel tools to address the role of GLI1 expression in breast carcinogenesis.

Citation Format: Jens H. Norum, Agneta Andersson, Maria Kasper, Therese Sørlie, Rune Toftgård. A transgenic mouse model for the Hedgehog pathway effector GLI1 induced mammary gland tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1407. doi:10.1158/1538-7445.AM2013-1407