The majority of estrogen receptor (ER)-positive breast cancers can be prevented by selective ER modulators (SERMs) such as tamoxifen and raloxifene. Yet to date, there are no available preventive therapies for ER-negative breast cancer, which accounts for 30-40% of human breast cancer. We have previously demonstrated that the transcription factor AP-1 transducer growth signals induced by multiple growth factors that are important for both ER-positive and ER-negative breast cells. Blockade of this factor by expressing a cJun dominant-negative mutant protein (Tam67) inhibits breast cancer cell growth in vitro. We now propose to determine whether long term in vivo blockade of the AP-1 transcription factor also inhibits mammary cell proliferation and suppresses breast tumorigenesis. We hypothesize that blockade of AP-1 in mouse mammary glands will suppress the development of ER-negative breast cancer induced by the oncogene erbB2. To address this question, we generated a transgenic mouse that expresses the Jun dominant-negative mutant under the control of a tetracycline-inducible promoter. We have mated these mice with an MMTV-reverse tetracycline-dependent transactivator mouse (MMTV-rtTA) to produce a bigenic, doxycycline (Dox)-inducible Tam67 mouse. These mice were then mated with MMTV-erbB2 mice that spontaneously develop ER-negative breast cancers. This mating produced trigenic mice that expressed an inducible Tam67 and the transforming oncogene erbB2 in the mammary gland. We then measured the time to tumor formation in these mice under AP-1-blocked or unblocked conditions. In vivo AP-1 blockade by Tam67 suppresses mammary epithelial cell proliferation and significantly delayed mammary tumor formation by more than 2 months as shown by Kaplan-Meier curves and assessed by the Generalized Wilcoxon test (p<0.0001). At the time po nt when 100% of the untreated animals had developed mammary tumors, only 4/14 (29%) of the Dox-treated mice developed tumors. The expression of erbB2 in the experimental mice was not affected by Tam67. Tumors that did arise in the AP-1 blocked animals failed to express the Jun dominant-negative protein, suggesting that resistance to AP-1 blockade occurs through downregulation of the expression of the cJun dominant-negative transgene. These findings demonstrate that blocking of AP-1 signaling suppresses oncogene-induced mammary cell transformation. We conclude that the AP-1 transcription factor is a critical transducer of oncogennc signals in breast cells. These results may provide scientific rationale to develop natural compounds and synthetic drugs that inhibit AP-1 to prevent ER-negative breast cancer in humans.
|Original language||English (US)|
|Journal||Cancer Epidemiology Biomarkers and Prevention|
|Issue number||11 SUPPL. and PART 2|
|State||Published - 2006|