Tissue structure, nuclear organization, and gene expression in normal and malignant breast

Because every cell within the body has the same genetic information, a sign ificant problem in biology is to understand how cells within a tissue expre ss genes selectively. A sophisticated network of physical and biochemical s ignals converge in a highly orchestrated manner to bring about the exquisit e regulation that governs gene expression in diverse tissues. Thus, the ult imate decision of a cell to proliferate, express tissue-specific genes, or apoptose must be a coordinated response to its adhesive, growth factor, and hormonal milieu. The unifying hypothesis examined in this overview is that the unit of function in higher organisms is neither the genome nor the cel l alone but the complex, three-dimensional tissue. This is because there ar e bidirectional connections between the components of the cellular microenv ironment (growth factors, hormones, and extracellular matrix) and the nucle us. These connections are made via membrane-bound receptors and transmitted to the nucleus, where the signals result in modifications to the nuclear m atrix and chromatin structure and lead to selective gene expression. Thus, cells need to be studied "in context", i.e., within a proper tissue structu re, if one is to understand the bidirectional pathways that connect the cel lular microenvironment and the genome, In the last decades, we have used well-characterized human and mouse mammar y cell lines in "designer microenvironments" to create an appropriate conte xt to study tissue-specific gene expression, The use of a three-dimensional culture assay, developed with reconstituted basement membrane, has allowed us to distinguish normal and malignant human breast cells easily and rapid ly. Whereas normal cells become growth arrested and form organized "acini," tumor cells continue to grow, pile up, and in general fail to respond to e xtracellular matrix and microenvironmental cues. By correcting the extracel lular matrix-receptor (integrin) signaling and balance, we have been able t o revert the malignant phenotype when a human breast tumor cell is cultured in, or on, a basement membrane. Most recently, we have shown that whereas beta 1 integrin and epidermal growth factor receptor signal transduction pa thways are integrated reciprocally in three-dimensional cultures, on tissue culture plastic (two-dimensional monolayers), these are not coordinated. F inally, we have demonstrated that, rather than passively reflecting changes in gene expression, nuclear organization itself can modulate cellular and tissue phenotype, We conclude that the structure of the tissue is dominant over the genome, and that we may need a new paradigm for how epithelial-spe cific genes are regulated ill vivo. We also argue that unless the structure of the tissue is critically altered, malignancy will not progress, even in the presence of multiple chromosomal mutations.