Induction of Mesechymal and Stem-Cell Traits in Breast Cancer Cells Via Heteroty

这项研究的重点是控制原发性乳腺癌是否会变得侵袭性、转移性并因此危及生命的分子机制。目前，预测这种侵袭性的能力还不完善，因为一组肿瘤的行为在个体之间存在很大的差异，这些肿瘤都被归类在乳腺癌的一个主要亚组中，因此被预测为共享共同的预后。目前，由于无法准确预测个体乳腺癌的未来行为，导致绝大多数确诊的肿瘤都得到了积极的治疗，而只有少数肿瘤注定会危及生命。这项研究描述了乳腺癌细胞恶性进展的三个主要决定因素，以及它们如何共同产生攻击性行为。这些是(I)癌细胞释放促炎信号的能力；(Ii)肿瘤间质内邻近的间充质干细胞对这些癌源信号的相互反应，继而导致有可能诱导癌细胞从上皮(良性)向间质(恶性)状态转移的信号的释放；以及(Iii)癌细胞通过经历这种分化状态的转变来对这些间质来源的信号做出反应的倾向，从而获得高度侵袭性的特征。癌细胞从上皮性/良性状态向间质/恶性状态转移的倾向似乎是由与 编码ZEB1的基因，ZEB1是上皮间充质状态的关键分子调节器。研究该基因的染色质构型--更确切地说，是与该基因启动子相关的组蛋白的共价修饰--有望揭示乳腺癌细胞激活其恶性转化程序的倾向，通常被称为上皮-间充质转化。

This research is focused on the molecular mechanisms that govern whether a primary breast cancer will or will not become aggressive, metastatic and thus life threatening. At present, the ability to predict such aggressiveness is imperfect, in that there is great inter-individual variability in the behavior of a group of tumors that are all classified together in one of the major subgroups of breast cancer and thus predicted to share a common prognosis. At present, this inability to generate accurate predictions of the future behavior of individual breast cancers leads to aggressive treatment of the great majority of diagnosed tumors, when only a minority are destined to become life threatening. The research describes three major determinants of malignant progression of breast cancer cells and how they conspire to generate aggressive behavior. These are (i) the ability of carcinoma cells to release pro-inflammatory signals; (ii) the reciprocal responses of nearby mesenchymal stem cells within the stroma of tumors to these carcinoma-derived signals, resulting secondarily in the release of signals that have the potential of inducing carcinoma cells to move from an epithelial(benign) to mesenchymal (malignant) state; and (iii) the propensity of the carcinoma cells to respond to these stroma-derived signals by undergoing this shift in differentiation state, thereby acquiring highly aggressive characteristics. The propensity of cancer cells to move from an epithelial/benign to a mesenchymal/malignant state appears to be governed by the state of the chromatin associated with the gene that encodes ZEB1, which functions as the key molecular governor of the epithelial vs. mesenchymal states. Examining the chromatin configuration of this gene- more specifically the covalent modifications of the histones associated with the promoter of this gene - holds the promise of revealing the proclivity of a breast cancer cell to activate its program of malignant conversion, often termed the epithelial-mesenchymal transition.