The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors

Abstract

The activating protein-1 (AP-1) transcription factor transduces growth signals through signal transduction pathways to the nucleus, leading to the expression of genes involved in growth and malignant transformation in many cell types. We have previously shown that overexpression of a dominant negative form of the cJun proto-oncogene, a cJun dominant negative mutant (Tam67), blocks AP-1 transcriptional activity, induces a G 1 cell cycle block and inhibits breast cancer cell growth in vitro and in vivo. We found that AP-1 blockade by Tam67 in MCF-7 breast cancer cells downregulates cyclin D1 transcriptional activity by at least two mechanisms: by suppressing transcription at the known AP-1 binding site (À934/À928) and by suppressing growth factor-induced expression through suppressing E2F activation at the E2F-responsive site (À726/À719). AP-1 blockade also led to reduced expression of E2F1 and E2F2, but not E2F4, at the mRNA and protein levels. Chromatin immunoprecipitation and supershift assays demonstrated that AP-1 blockade caused decreased binding of E2F1 protein to the E2F site in the cyclin D1 promoter. We also found that Tam67 suppressed the expression of the E2F1 dimerizing partner, DP1 and E2F-upregulated cell cycle genes (cyclins E, A, B and D3) and enhanced the expression of E2F-downregulated cell cycle genes (cyclins G 2 and I). Reduced expression of other E2F-regulated genes was also seen with AP-1 blockade and E2F suppression. Thus, the AP-1 factor regulates the expression of cyclin D and E2F (the latter in turn regulates E2F-downstream genes), leading to cell cycle progression and breast cancer cell proliferation.

The Regulatory Mechanism of the LY6K Gene Expression in Human Breast Cancer Cells

“…More recent studies have been carried out to identify the relationship between AP-1 transcription factors and breast cancer cells. Studies reported to date suggest that AP-1 plays a critical role in breast cancer, including breast cell transformation and breast cancer cell growth, proliferation, survival, invasion, and metastasis (29,30). Based on our results, we suggest that the AP-1 family members JunD and Fra-1 play an important role in cell mobility of breast cancer cells by promoting LY6K gene expression.…”

CAPER, a novel regulator of human breast cancer progression

“…46 Importantly, AP-1/c-Jun has previously been shown to regulate human breast cancer cell proliferation. [47][48][49] For instance, overexpression of c-Jun was shown to increase the tumorigenic and invasive potentials of MCF-7 cells in both in vitro and in vivo settings. 47 Conversely, inhibition of AP-1/c-Jun transcriptional activity in MCF-7 cells through expression of a c-Jun dominant-negative mutant (Tam67) was shown to suppress cyclin D1 expression, block cell cycle progression, and inhibit MCF-7 cell proliferation in vitro.…”

“…47 Conversely, inhibition of AP-1/c-Jun transcriptional activity in MCF-7 cells through expression of a c-Jun dominant-negative mutant (Tam67) was shown to suppress cyclin D1 expression, block cell cycle progression, and inhibit MCF-7 cell proliferation in vitro. 48,49 Inhibition of AP-1/c-Jun transcriptional activity was also shown to suppress MCF-7 cell growth in xenograft mouse models. 48 Phosphorylation of c-Jun at ser63 and ser73 residues by kinases such as the c-Jun N-terminal kinase (JNK) was shown to be required for AP-1/cJun transcriptional activity.…”

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

“…It is also shown to regulate E2F-dependent genes such as cyclins and cell proliferation regulators (28,35). We recently showed that AP-1 cross-talks with ER (2,36).…”