Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations.

Adenoid cystic carcinoma (ACC) of the breast with a predominant solid pattern is difficult to diagnose with certainty and differentiate from more common triple-negative breast cancers (TNBCs) of basal-phenotype. To better characterize solid ACC, we performed a clinical, morphological, immunohistochemical, and molecular comparative analysis of 33 ACCs of the breast comprising 17 solid variant ACCs and 16 conventional ACCs. Solid ACCs displayed basaloid morphology with an exclusive or predominant epithelial cell population associated with decreased myoepithelial differentiation, while demonstrating MYB protein overexpression similar to the more common type of ACC. Strong and diffuse MYB expression by immunochemistry was observed in 14/17 (82%) of solid ACCs while MYB rearrangements were detected by break apart fluorescence in situ hybridization (FISH) in only 3/16 (19%) of solid ACCs. Conversely, weak MYB immunohistochemical expression was observed in only 7/204 (3%) of TNBC. Solid ACCs displayed a transcriptomic profile distinct from conventional ACCs with 549 genes showing a highly significant differential expression between conventional and solid ACC [false discovery rate (FDR) < 0.01; log2FC > |1|]. EnrichR and Kegg Pathway analyses identified PI3K-Akt and focal adhesion signaling pathways as significantly overexpressed in conventional ACCs compared with solid ACCs which significantly overexpressed the nitrogen metabolism pathway. CREBBP mutations and NOTCH activating gene mutations were only present in solid ACCs, concerning 5/16 (31%) of cases for each gene. Tumors with NOTCH activating mutations displayed a strong diffuse nuclear NICD1 staining, an established marker of Notch pathway activation. Solid ACCs also differed from basal-type TNBC, with fewer TP53 mutations and a more stable genomic profile on array comparative genomic hybridization (CGH). In summary, solid-type ACC of the breast is a distinct molecular entity within the ACC family and is different from common basal-type TNBC. MYB is a diagnostically useful biomarker of solid ACC and NOTCH could be a novel potential therapeutic target in 30% of cases.

Protective effects of dietary curcumin in mouse model of chemically induced colitis are strain dependent.

BACKGROUND: Curcumin (diferulolylmethane) has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. Trinitrobenzene sulfonic acid (TNBS) colitis in NKT-deficient SJL/J mice has been described as Th1-mediated inflammation, whereas BALB/c mice are believed to exhibit a mixed Th1/Th2 response. METHODS: We therefore investigated the effect of dietary curcumin in colitis induced in these 2 strains. RESULTS: In the BALB/c mice, curcumin significantly increased survival, prevented weight loss, and normalized disease activity. In the SJL/J mice, curcumin demonstrated no protective effects. Genomewide microarray analysis of colonic gene expression was employed to define the differential effect of curcumin in these 2 strains. This analysis not only confirmed the disparate responses of the 2 strains to curcumin but also indicated different responses to TNBS. Curcumin inhibited proliferation of splenocytes from naive BALB/c mice but not SJL/J mice when nonspecifically stimulated in vitro with concanavalin A (ConA). Proliferation of CD4(+) splenocytes was inhibited in both strains, albeit with about a 2-fold higher IC(50) in SJL/J mice. Secretion of IL-4 and IL-5 by CD4(+) lymphocytes of BALB/c mice but not SJL/J mice was significantly augmented by ConA and reduced to control levels by curcumin. CONCLUSIONS: The efficacy of dietary curcumin in TNBS colitis varies in BALB/c and SJL/J mouse strains. Although the exact mechanism underlying these differences is unclear, the results suggest that the therapeutic value of dietary curcumin may differ depending on the nature of immune dysregulation in IBD.