cJun overexpression in MCF-7 breast cancer cells produces a tumorigenic, invasive and hormone resistant phenotype

Abstract

We have previously demonstrated decreased Jun/AP-1 activity in the breast cancer cell line MCF-7 when compared to normal or immortalized mammary epithelial cells. In this paper, we overexpress Jun in MCF-7 cells (MCF7Jun) and demonstrate that it results in diverse biologic and biochemical changes, which mimic those seen clinically in breast cancer. Overexpression of Jun causes signi®cant alterations in the composition of AP-1, decreased junB and increased fra-1 expression and results in an increased biologic aggressiveness. MCF7Jun cells exhibit increased cellular motility, increased expression of a matrix degrading enzyme MMP-9, increased in vitro chemoinvasion and tumor formation in nude mice in the absence of exogenous estrogens. Furthermore, MCF7Jun cells are unresponsive to the growth stimulating e ects of estrogen and growth inhibitory e ects of tamoxifen. Analysis of the estrogen receptor (ER) expression and activity showed that the MCF7Jun cells have no detectable ER. MCF-7 cells overexpressing mutant forms of cJun were responsive to the growth stimulatory e ects of estrogen indicating that full-length cJun is required to acquire the estrogenindependent phenotype in breast cancer cells.

AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity

“…We have found that AP-1 inhibition induced by TAM67 sensitizes MCF7 breast cancer cells to apoptosis when these cells are starved of serum (unpublished observation). Previous data results showing that reducing AP-1 activity in breast cancer cells caused increased cell death after treatment with UV light or cisplatin chemotherapy are consistent with these results (Sauter et al, 1999;Smith et al, 1999;Potapova et al, 2001).…”

“…The cyclin D1 and cyclin E mRNA level was measured by performing RPA. TAM67 decreased the expression of cyclins mRNA including cyclin D's (a), but did not affect the expression level of cyclin E mRNA (b) Smith et al, 1999), chemotherapy resistance (Potapova et al, 2001), and tamoxifen resistance (Schiff et al, 2000). We have also shown that AP-1 blockade induced by TAM67 suppresses AP-1 activity induced by different peptide growth factors, including EGF, IGF-1, heregulin-b, b-FGF, and estrogen.…”

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

“…E-cadherin inactivation mechanism and EMT in breast cancer M Lombaerts et al proliferation, malignant transformation and aggressiveness of cells (Mechta et al, 1997;Smith et al, 1999). Detectable FOSL1 protein expression in mammary carcinomas was demonstrated to be associated with poor differentiation, Ki67 and cyclin E expression and an oestrogen receptor-negative phenotype (Milde-Langosch et al, 2000).…”

Jun, the oncoprotein

“…Besides the standard indicators of oncogenicity, such as multilayered growth on solid substrates, growth in low serum concentrations, anchorage-independence, and tumorigenicity, Jun also induces more subtle changes. Jun-expressing cells show increased motility and invasiveness Smith et al, 1999). In mammary epithelial cells, Jun induces the loss of polarity accompanied by a dissociation of beta-catenin from E-cadherin, redistribution of beta-catenin and a disruption of intercellular junctions (Fialka et al, 1996).…”

“…Formally, this is a co-transformation but Jun and Fra-1 probably form AP-1 dimers which qualify as a single oncogenic e ector. Overexpression of c-Jun greatly enhances the tumorigenic properties of the MCF7 human mammary carcinoma cell line, inducing elevated motility, unresponsiveness to estrogen and tamoxifen, and increased tumor formation in nude mice (Doucas et al, 1991;Smith et al, 1999). v-Jun can transform the mouse ®broblast cell line C3H10T1/ 2 (Cohen et al, 2001).…”