Targeting the Activator Protein 1 Transcription Factor for the Prevention of Estrogen Receptor–Negative Mammary Tumors

Abstract

The oncogene erbB2 is overexpressed in 20% to 30% human breast cancers and is most commonly overexpressed in estrogen receptor (ER)-negative breast cancers. Transgenic mice expressing erbB2 develop ER-negative mammary tumors, mimicking human breast carcinogenesis. Previously, we have shown that activator protein 1 (AP-1) regulates proliferation of ER-negative breast cancer cells. We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER-negative tumorigenesis induced by erbB2. Trigenic erbB2 mice were generated by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to a MMTV-erbB2 mouse. The resulting trigenic mice develop tumors and express a doxycycline-inducible c-Jun dominant negative mutant (Tam67) in the mammary glands. In vivo AP-1 blockade by Tam67 expression started delayed mammary tumor formation in MMTVerbB2 mice by more than 11 weeks. By 52 weeks of age, 100% (18 of 18) of the untreated animals had developed mammary tumors, whereas 56% (9 of 16) of the doxycycline-treated trigenic mice developed tumors. In addition, the tumors that arose in the AP-1-blocked erbB2 mice failed to express Tam67. Twenty-five percent of the doxycycline-treated MMTV-erbB2 mice survived more than 72 weeks of age without developing mammary tumors. Examination of normal-appearing mammary glands from these mice showed that AP-1 blockade by Tam67 also significantly prevents the development of premalignant lesions in these glands. The expression of erbB2 either in normal mammary tissue or in mammary tumors was not altered. Our results show that blocking the AP-1 signaling in mammary cells suppresses erbB2-induced transformation, and show that the AP-1 transcription factor is a critical transducer of erbB2. These results provide a scientific rationale to develop targeted drugs that inhibit AP-1 to prevent the development of ER-negative breast cancer.Despite the cancer-preventive activity of selective estrogen receptor (ER) modulators and the aromatase inhibitors, it is clear that none of these hormonal therapies prevent all breast cancers. In breast cancer prevention trials testing hormonal therapies, many ER-positive breast cancers were prevented; however, none of the ER-negative breast cancers was prevented (1). Thus, more effective agents for the prevention of ER-negative breast cancer are urgently needed. The results of many prevention trials show the feasibility of preventing breast cancer using medical therapy. However, they also show that more effective agents are needed.In addition to estrogen, many other growth factors have been shown to be critical growth regulators for breast cells. ER-negative breast cancer often requires peptide growth factors to support their growth. The growth factors and their receptors offer potential targets for the treatment and prevention of breast cancer. One such growth factor receptor, erbB2, has already been effectively targeted to treat those breast cancers that overexpress this protein. We have previously targeted the epidermal growth factor receptor usin...

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