This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.According to the American Cancer Society, approximately one out of two among men and one out of three among women will develop cancer at some point during the course of their lifetime in the U.S. Cancer cells exhibit many defects in intracellular and intercellular communication that contribute to the loss of tissue homeostasis (excess cell proliferation, invasion, and metastasis). Intercellular communication in many organs is maintained via intercellular gap junction channels (GJIC) allow the transfer of small molecules which may regulate cell growth, differentiation, and function. Gap junctions are the only communicating junctions found in animal tissues, in all species, which are responsible for the direct traffic of ions and molecules with molecular weights less than 1,200 Daltons. These traffic ways are formed by the interaction between two hemichannels on the surface of opposing cells. These hemichannels are formed by the association of six proteins, the connexins. Because of the importance of intercellular junctions in the maintenance of the cellular homeostasis, the modulation of intercellular junctions and expression of connexin seems to be involved in carcinogenesis. Stable abnormal regulation of gap junction function has been associated with the activation of several oncogenes. Several tumor suppressor genes have also been associated with the up-regulation of gap junction function. Since gap junctions exist in all organs of multi-cellular organisms, the dysfunction of these gap junctions by various toxic chemicals which have cell type/tissue/organ specificity could bring about very distinct clinical consequences, such as embryo lethality or teratogenesis, reproductive dysfunction in the gonads, neurotoxicity of the central nervous system, hyperplasia of the skin, and tumor promotion of initiated tissue. Recent investigations demonstrate that our environment is contaminated with many endocrine disruptors, which can interfere with the endocrine systems and adversely effect hormone balance or disrupt normal function, eventually leading to detrimental effects in the reproductive and developmental processes. Many hydrocarbons and organochlorine compounds are environmental pollutants that have been shown to downregulate gap junctions. The regulation of gap junction by these hydrocarbon compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its derivatives are unclear in cancer formation. Thus, understanding how TCDD affects gap junctional intercellular communication and subsequently interfere with cell homeostasis will provide valuable evidence of biochemical mechanisms of action. We hypothesize that TCDD regulates gap junction activity via PKC signal pathway and subsequently inhibits gap junction activity in epithelial breast cancer cells.
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