FosB is Highly Expressed in Normal Mammary Epithelia, but Down-Regulated in Poorly Differentiated Breast Carcinomas

Abstract

FosB is a member of the AP-1 family of transcription factors which represent important regulators of cell proliferation and differentiation. Based on prior results which indicated a role of FosB in breast cancer, we studied FosB protein and mRNA expression by immunohistochemistry and, partly, in situ hybridization in 68 mammary carcinomas and normal breast tissues. We found strong nuclear FosB immunoreactivity in epithelial cells of normal lobules and ducts, whereas carcinomas frequently showed loss of FosB expression (n = 8) or weak immunostaining (n = 24). Reduced FosB protein expression in tumors correlated with high grading (p = 0.005), negative estrogen and progesterone receptor status (p < 0.001), and strong HER2/neu expression (p = 0.025). Comparison with expression of seven cell-cycle regulators revealed an association of low/absent FosB staining with p16MTS1 overexpression (p = 0.005). RT-PCR showed expression of full-length FosB and the smaller splice variant FosB2 in most carcinomas and cell lines with and without FosB protein expression, indicating that both proteins are differentially regulated mainly at a post-transcriptional level. By sequence analysis of the coding region in four cell lines and 17 carcinomas we detected a mutation in HBL-100 cells. Our results indicate that high FosB expression might be necessary for normal proliferation and differentiation of mammary epithelial cells, and reduced FosB protein levels might be involved in dedifferentiation during breast tumorigenesis.

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

“…Our own prior investigations have shown that FosB is highly expressed in more differentiated, hormone-receptor-positive tumours (Milde-Langosch et al, 2003). Thus, the comparison of p-ERK expression with AP-1 protein results confirms our conclusion that overexpression of these activated MAP kinases is associated with a better prognosis.…”

Apigenin inhibits PMA-induced expression of pro-inflammatory cytokines and AP-1 factors in A549 cells

“…In normal lobular and ducts, the epithelial cells show higher expression of FosB mRNA and protein, whereas in majority of carcinomas and MCF-7 cells less of FosB protein was expressed [40], and this is in agreement with our study using A549 cells where little or no FosB mRNA expression was observed.…”

Possible involvement of FosB in (–)-xanthatin-mediated anti-proliferative effects in human cancer MDA-MB-231 cells

“…In the present study, FosB, which may be involved in changing mammary epithelial cells into poorly differentiated breast cancer cells (Milde-Langosch et al, 2003), has been suggested to be one of the molecular targets of cell death signaling stimulated by (-)-xanthatin (Fig. 4), and (-)-xanthatin may also have multiple action points to attack cancer cells, indicating its potential as a lead com- A working model of (-)-xanthatin-mediated cell death is described in combination with a previous study (Milde-Langosch et al, 2003).…”

“…4), and (-)-xanthatin may also have multiple action points to attack cancer cells, indicating its potential as a lead com- A working model of (-)-xanthatin-mediated cell death is described in combination with a previous study (Milde-Langosch et al, 2003). As shown in the Figure, (-)-xanthatin may evoke cell death through the up-regulation of FosB, which is down-regulated in poorly differentiated breast cancer cells (MildeLangosch et al, 2003).…”

“…FosB, a member of the AP-1 (activator protein-1) family of transcription factors involved in the regulation of cell proliferation/differentiation, has been suggested to play an important role in the normal proliferation/differentiation of mammary epithelial cells, and the down-regulation of FosB has been shown to participate in the dedifferentiation of breast tumorigenesis (Milde-Langosch et al, 2003). Based on this phenomenon, one possibility may be that chemicals up-regulating the molecule of FosB effectively suppress the proliferation of poorly differentiated breast cancer cells, such as triple negative highly invasive MDA-MB-231 cells.…”