Blockade of the AP-1 transcription factor prevents wnt1-induced, but not c-myc-induced mammary tumors in mice

A145

Multiple oncogenes such as erbB2, wnt-1, and c-myc are overexpressed or mutated in human breast cancers. Transgenic mice expressing these oncogenes develop tumors in the mammary glands, mimicking human breast carcinogenesis. We have attempted to block mammary tumorigenesis in these mice by targeting the AP-1 transcription factor. Previously we have demonstrated that the AP-1 transcription factor regulates proliferation of both estrogen receptor (ER)-positive and ER-negative breast cancer cells. We also demonstrated that in vivo inducible expression of Tam67, a cJun dominant negative mutant, suppresses mammary gland development. We further demonstrated that AP-1 blockade by Tam67 delayed and partially prevented erbB2-induced mouse mammary tumor formation. For this study, we hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppresse tumor development induced by two other oncogenes Wnt1 and cMyc. To address this hypothesis, we generated trigenic Wnt1 and cMyc mice by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to MMTV-wnt1 or MMTV-c-myc mouse. The resulting trigenic mice develop tumors and express inducible Tam67 in the mammary glands. AP-1 blockade was induced at 3 month of age when mammary glands were fully developed. At the time point (28 weeks) when 100% of the control wnt1 mice (10/10) had developed mammary tumors, only 1/12 (8%) of the Dox-treated mice developed tumor. AP-1 blockade in the mammary gland significantly prevented wnt1-induce mammary tumor formation as shown by Kaplan-Meier curves and assessed by the Generalized Wilcoxon test (p<0.0001). For c-myc transgenic mice, AP-1 blockade did not significantly delay median time to mammary tumor formation (p = 0.2644). Our findings demonstrate that blocking AP-1 signaling suppresses wnt1-induced, but not c-myc-induced mammary cell transformation. We conclude that the AP-1 transcription factor is a critical transducer of Wnt1 but not cMyc oncogenic signals in breast cells. These results provide scientific rationale to develop targeted drugs that inhibit AP-1 to prevent ER-positive and ER-negative breast cancer in humans. This work is supported by a grant from the Dan L. Duncan Cancer Center at Baylor College of Medicine and an NIH R01 grant CA123246.