The prognostic significance of tumor-associated FOXP3(+) regulatory T cells (Tregs) and CD8(+) cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas is studied. Tregs and CTLs were assessed by immunohistochemistry in 1270 cases of invasive breast carcinoma for their associations with patient survival, histopathologic features, and molecular subtypes. Infiltrates of Tregs and CTLs were observed within tumor bed and in the tissue surrounding tumor. Within tumor bed, increased infiltration of Tregs and CTLs was significantly more common in those with unfavorable histologic features, including high histologic grade and negative ER and PR status. In addition, high density Treg infiltration was also associated with tumor HER2 overexpression, decreased overall survival (OS) and progression-free survival (PFS). In tissue surrounding tumor, in contrast, high CTL/Treg ratio was found to be significantly associated with improved OS and PFS. These prognostic associations were confirmed by multivariate analysis. Furthermore, the density of Treg infiltrates within tumors was inversely correlated with the prognosis of the molecular subtypes of tumors. The ratio of CTL/Treg infiltrates in the surrounding tissue was also significantly higher in luminal than non-luminal subtypes of carcinoma. The prognostic significances of Tregs and CTLs in breast carcinoma depend on their relative density and location. The density of intratumoral Treg infiltrates and the peritumoral CTL/Treg ratio are independent prognostic factors and correlated with the prognosis of the molecular subtypes of breast carcinoma, which may serve as potential target for stratifying immunotherapy to battle against the aggressive subtypes of breast carcinoma.

It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G 1 /S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.histone methylation | breast cancer R ecent studies indicate that, analogous to other covalent histone modifications such as acetylation, histone methylation is reversible. However, in contrast to histone acetylation, which is generally associated with active transcription, histone methylation can be associated with either activation or repression of transcription, depending on what effector protein is recruited (1). Even within the same lysine residue, the biological consequences of methylation seem to be variable. For example, methylation of histone H3 lysine 9 (H3K9), long considered a hallmark of heterochromatin (2-8), was recently found to also be present at the transcribed regions of active mammalian genes (9, 10), suggesting that certain methyl marks can have multiple functions in the cell.Given the complexity of histone methylation modification, the integration and/or coordination of methylation/demethylation in a particular biological process becomes an issue of great importance in further understanding the role of histone methylation in nucleosome functioning. Specifically, actively transcribed genes, including the ones that are regulated by estrogen receptor (ER) (11-13), are marked by methylation at histone H3K4, but at the same time by demethylation at H3K9; H3K4 and H3K9 methylation levels are mutually exclusive, and this relationship is conserved from fission yeast to humans. How opposed H3K4 methylation and H3K9 demethylation are achieved and coordinated in transcription activation in mammalian cells is not fully understood.H3K4 methylation is deposited by a family of histone methyltransferases (HMT) that share a conserved SET (Su(var), E(z), and Trithorax) domain. In mammalian cells, multiple HMTs have been characterized: SET1A and SE...

MCP-1 acts as a paracrine and autocrine factor for CaP growth and invasion.

Vasculogenic mimicry (VM) refers to the unique capability of aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. In the study we demonstrated that CD133 expression was the highest in triple-negative (TN) breast cancer specimens. Importantly, VM showed statistical correlation with CD133(+) expression. The presence of the close relationship between VM and CD133(+) expression might be central for TN tumor relapse and progression. The TN breast cancer cell line, MDA-MB-231 cells developed a range of colony morphologies paralleling the holoclone, meroclone and paraclone morphologies produced by normal keratinocytes and other epithelial cancer cell lines when plated at clonal densities. Holoclone cells were capable of forming more colonies on soft agar than meroclone cells and paraclone cells, suggesting that holoclone cells had higher self-renew potential and might harbors cancer stem cells (CSCs) subpopulation. Strikingly, it was holoclone that displayed CD133(+) phenotype and formed VM. In addition, holoclone acquired endothelial cell marker vascular endothelial-cadherin expression and upregulated VM mediators matrix metalloproteinase (MMP)-2 and MMP-9 expression. The subpopulation with holoclone morphology, CD133(+) phenotype and CSCs characteristics might have the capacity of transdifferentiation and contributed to VM in TN breast cancer. The related molecular pathways may be used as novel therapeutic targets for the inhibition of angiogenesis and metastasis in TN breast carcinoma.

RKIP does not influence the tumorigenic properties of human prostate cancer cells. It appears to be a novel and clinically relevant suppressor of metastasis that may function by decreasing vascular invasion.