MODULATION OF CELL-CELL COMMUNICATION IN BREAST CANCER

细胞间通过缝隙连接的直接通讯代表了 向高度分化的 多细胞生物在转化或癌细胞中， 细胞间通讯的异常。间隙连接的重新安装 通过调节剂的通信已经在转化的 包括我们在内的调查人员使用二甲基亚砜和环状 AMP体外治疗，我们的实验室能够将非传染性， 非增殖依赖性小鼠乳腺肿瘤细胞转化为肿瘤， 他莫昔芬治疗，并成为传染性的，如所示的染料 转移技术这项建议的具体目的是扩大 实验涉及以下三个领域： (1)差距结的电导已被证明是门控的 几个因素，其中之一是细胞内钙离子水平。的 所提出的研究是调节人类的细胞-细胞通讯， 乳腺癌细胞（a）通过影响细胞内钙的试剂 水平通过三个独立的，但相互作用的系统，即环AMP， 钙调蛋白和蛋白激酶C系统，和（B）通过使用 针对差距连接蛋白的单克隆抗体。荧光黄 通过刮载、显微注射和荧光转移染料 光漂白后再分布（FRAP）技术将用于 确定主加载单元之间的转移速率，以及 邻近细胞，细胞内钙离子水平将 监测。 (2)也有越来越多的赞赏的概念， 乳腺的组成部分在生长中起着重要作用 乳腺癌的治疗因此，传播学也将 在乳腺癌细胞和正常基质细胞之间进行，和 乳腺癌和转化的基质细胞之间的关系 共培养系统调节剂对这种相互作用的影响 并评估对胶原酶和透明质酸盐产生的影响。 (3)这项提案还将研究雌激素与 受体（ER）阳性和阴性乳腺癌细胞，并评估是否 这种调节将改变这两种细胞群的生长平衡 在共培养系统中。 通过改变细胞间通讯和细胞行为的程度， 这些调节剂可延缓肿瘤细胞生长并最终导致 延长乳腺癌患者的生存期。

Direct communication between cells via gap junctions represents an important evolutionary step towards formation of highly differentiated multicellular organisms. In transformed or cancerous cells there is an aberration of intercellular communication. Re-installment of gap junctional communication by modulating agents has been demonstrated in transformed cells by investigators including us. Using dimethyl sulfoxide and cyclic AMP in vitro treatment, our laboratory was able to convert noncommunicable, hormone-independent mouse mammary tumor cells to tumors which regressed on tamoxifen therapy and become communicable as illustrated by the dye transfer technique. The specific aims of this proposal are to extend the experiments to the following three fields: (1) The conductance of the gap junction has been shown to be gated by several factors, one of which is the intracellular calcium ion level. The proposed studies are to modulate the cell-cell communication of human breast cancer cells (a) by agents which affect the intracellular calcium level through three separate but interacted systems, namely the cyclic-AMP, the calmodulin and the protein kinase C systems, and (b) by the use of monoclonal antibodies against the gap junctional proteins. Lucifer yellow dye transfer by the scrape-load, the microinjection and the fluorescence redistribution after photobleaching (FRAP) techniques will be used to determine the rate of transfer between the primary loading cells and neighboring cells, and the intracellular calcium ion level will be monitored. (2) There is also growing appreciation of the concept that the stromal component of the mammary gland plays an important role in the growth regulation of breast cancer. Therefore, the communication study will also be performed between breast cancer cells and normal stromal cells, and between breast cancer and transformed stromal cells in an in vitro coculture system. The influence of modulating agents on such interaction and on the collagenase and hyaluronate production will be assessed. (3) This proposal will also examine the interaction between estrogen receptor (ER) positive and negative breast cancer cells and assess whether such modulation will alter the growth balance of these two cell populations in the coculture system. By changing the degree of cell-cell communication and cellular behavior, these modulating agents may retard tumor cell growth and ultimately result in a prolongation of survival in patients with breast cancer.