Expression of small breast epithelial mucin (SBEM) protein in tissue microarrays (TMAs) of primary invasive breast cancersAims: Small breast epithelial mucin (SBEM) is a recently described gene product that shows promise as a new breast biomarker. The aim was to investigate for the first time SBEM protein expression in a large cohort (n = 300) of invasive breast cancers, its relationship to established clinical variables and its association with clinical outcome. Methods and results: Immunohistochemical analysis was performed on tissue microarrays consisting of 149 oestrogen receptor (ER) a) and 151 ERa+ breast cancers. Overall, 18% of tumours were SBEM+ (n = 53 ⁄ 300). However, SBEM protein was more frequently observed in ER) (22%) than in ER+ cancers (13%; P = 0.049). A significant association with psoriasin ⁄ S100A7 expression (P £ 0.0001) was observed in the entire cohort. SBEM was also positively associated with HER-2 (P = 0.046) in ER) cancers, and increased levels of SBEM were strongly associated with higher tumour grade (P = 0.0015). Furthermore, SBEM expression showed a trend towards an association with reduced overall survival and relapse-free survival in the ER+ cohort (P = 0.063 and P = 0.072, respectively). Conclusions: Our results suggest that SBEM may identify a unique subset of breast cancers with poor prognosis and may have future implications for therapeutic management of this disease.

Intestinal epithelial cells participate in the acute phase response in response to inflammation. We have shown that acute phase protein genes are induced during intestinal acute phase response, and that the CCAAT/enhancer binding protein family of transcription factors are involved. To address the role of specific C/EBP isoforms, we generated IEC-6 rat intestinal epithelial cell lines expressing different C/EBP isoforms, by retroviral infection. Overexpression of C/EBP␣ p30 and C/EBP␦ led to increases in C/EBP␤ LAP and C/EBP␤ LIP endogenous protein levels, as determined by electrophoretic mobility shift assays and Western blot. Inhibition of C/EBP activity with dominant negative C/EBPs (C/EBP␤ LIP, 3hF, 4hF) decreased glucocorticoid-, cAMP-and IL-1 responsiveness of the endogenous haptoglobin gene, while overexpression of each C/EBP isoform increased the responsiveness to these regulators. In contrast, dominant negative C/EBPs or C/EBP isoforms did not alter the expression of ␣-acid glycoprotein in response to dexamethasone and of C/EBP␤ and C/EBP␦ in response to various regulators as assessed by Northern blot. These data show that the three C/EBP isoforms are involved in the regulation of haptoglobin and that C/EBP␤, C/EBP␦, and ␣-acid glycoprotein expression are not induced by C/EBP isoforms in contrast to other cell types. C/EBP␤ LAP-expressing cells showed an inhibition of cell growth characterized by a delay in p27Kip1 decrease in response to serum and a decrease in cyclin D isoforms and cyclin E protein levels. Finally, C/EBP isoforms interact with the E2F4 transcription factor. Thus, specific C/EBP isoforms are involved in the differential expression of acute phase protein genes in response to hormones and cytokines. Furthermore, C/EBP isoforms may play a role in the control of cell cycle progression.

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To study this immunoregulatory effect more directly, we induced acute GVH reactions in which we treated the donors rather than the recipients with palifermin. The recipient mice were protected from GVHD-associated morbidity, and their cytokine profile was predominantly Th2. The palifermin-treated donor mice alone showed a similar Th2 cytokine profile, and we observed elevated levels of thymic stromal lymphopoietin mRNA in the thymus. We further demonstrated that treating the donor mice with palifermin protects against GVHD-associated morbidity, even if the donors are deficient in Valpha14i natural killer T cells. Our findings clearly show that palifermin mediates immunoregulatory effects in addition to its cytoprotective effects and that both are likely to be involved in the mechanism through which palifermin provides protection from acute murine GVHD.