MODULATION OF CELL-CELL COMMUNICATION IN BREAST CANCER

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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.