Adipocytes are the most abundant stromal partners in breast tissue. However, the crosstalk between breast cancer cells and adipocytes has been given less attention compared to cancer-associated fibroblasts. Here we find, through systematic screening, that primary mammary gland-derived adipocytes (MGDAs) promote growth of breast cancer cells that express monocarboxylate transporter 2 (MCT2) both in vitro and in vivo. We show that β-hydroxybutyrate is secreted by MGDAs and is required to enhance breast cancer cells malignancy in vitro. Consistently, β-hydroxybutyrate is sufficient to promote tumorigenesis of a mouse xenograft model of MCT2-expressing breast cancer cells. Mechanistically we observe that upon co-culturing with MGDAs or treatment with β-hydroxybutyrate, breast cancer cells expressing MCT2 increase the global histone H3K9 acetylation and upregulate several tumour-promoting genes. These results suggest that adipocytes promote malignancy of MCT2-expressing breast cancer via β-hydroxybutyrate potentially by inducing the epigenetic upregulation of tumour-promoting genes.

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial−mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.

Insulin-like growth factor 1 (IGF-1) inhibits 5-fluorouracil (5-Fu)-induced apoptosis in esophageal carcinoma cells; however, the mechanisms for IGF-1-induced 5-Fu chemoresistance remain unknown. In the human esophageal carcinoma cell line, CE48T/VGH, we show that IGF-1 up-regulated survivin expression at the post-transcriptional level and this up-regulation is mediated by both the PI3-K/Akt and casein kinase 2 signaling pathways. We then examine whether IGF-1-induced 5-Fu chemoresistance is mediated through up-regulation of survivin. Ectopic expression of survivin inhibits 5-Fu-induced apoptosis; furthermore, the abolition of survivin expression sensitizes cells to 5-Fu treatment and prevents the anti-apoptotic function of IGF-1 in esophageal carcinoma cell lines. We also found that ectopic expression of survivin or treatment with IGF-1 inhibits the release of Smac/DIABLO and caspases activation after 5-Fu treatment. Our results strongly suggest that IGF-1 inhibits 5-Fu induced apoptosis through increasing survivin levels, which prevents Smac/DIABLO release and blocks the activation of caspases. Therefore, up-regulation of IGF-1 and survivin would seem to be responsible for 5-Fu chemoresistance in esophageal cancer patients and these factors may be the valuable predictors of 5-Fu chemoresistance in esophageal carcinoma.

reasonable electrical conductibility. The Sn-Pb solder is a The solder bump interconnection is originated by IBM in 2-phase system. It represents typical phase diagram for binary the early 1960s and Flip chip technology became popular in eutectic systems, as the figure 1. The eutectic represents the packaging. Comparing with conventional wire bonding point where that composition goes directly from solid to interconnection package method, flip chip interconnection can liquid, i.e. without partially melting to a solid-liquid offer excellent electrical performance, very small chip size combination. The major characteristic is that a mixture of packages and high input/output handling capability. Recently, substance having a minimum melting point. Hence, organic substrates have replaced conventional ceramic 63Sn/37Pb of the eutectic composition is most commonly substrate. It is due to that the organic substrate can provide a used joint material for Integrated Circuit (IC) due to 1830C of minimal board area requirement, such as a reduction in weight the minimum melting point [1]. and height profile. Therefore, the interconnection of flip chip capability of the bumping process and the capability of the target substrate technology to route the die pitch. The Key~~~~~~wod:ftge'lpCi,9P/5 up connection of high Pb bump to ceramic iS accomplished by high temperature reflow, typically at temperature of 350°C or

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