Tissue structure, nuclear organization and gene expression in normal and malignant breast
Because every cell within the body has the same genetic information, a significant problem in biology is to understand how cells within a tissue express genes selectively. A sophisticated network of physical and biochemical signals converge in a highly orchestrated manner to bring about the exquisite regulation that governs gene expression in diverse tissues. Thus, the ultimate 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 cell alone but the complex, three-dimensional tissue. This is because there are bidirectional connections between the components of the cellular microenvironment (growth factors, hormones, and extracellular matrix) and the nucl2048 These connections are made via membrane-bound receptors and transmitted to the nucleus, where the signals result in modifications to the nuclear matrix and chromatin structure and lead to selective gene expression. Thus, cells need to be studied in context, i.e. within a proper tissue structure if one is to understand the bidirectional pathways that connect the cellular microenvironment and the genome. In the last decades, researchers have used well-characterized human and mouse mammary cell lines in designer microenvironments to create an appropriate context to study tissue-specific gene expression. The use of a three-dimensional culture assay, developed with reconstituted basement membrane, has allowed them to distinguish normal and malignant human breast cells easily and rapidly. Whereas normal cells become growth arrested and form organized acini, tumor cells continue to grow, pile up, and in general fail to respond to extracellular matrix and microenvironmental cues. By correcting the extracellular matrix-receptor (integrin) signaling and balance, they have been able to revert the malignant phenotype when a human breast tumor cell is cultured in, or on, a basement membrane. Most recently, they have shown that whereas beta integrin and epidermal growth factor receptor signal transduction pathways are integrated reciprocally in three-dimensional cultures, on tissue culture plastic (two-dimensional monolayers), these are not coordinated. Finally, they have demonstrated that, rather than passively reflecting changes in gene expression, nuclear organization itself can modulate cellular and tissue phenotype. The authors conclude that the structure of the tissue is dominant over the genome, and that they may need a new paradigm for how epithelial-specific genes are regulated in vivo. They also argue that unless the structure of the tissue is critically altered, malignancy will not progress, even in the presence of multiple chromosomal mutations.
- Research Organization:
- Lawrence Berkeley National Lab., CA (United States)
- Sponsoring Organization:
- USDOE Director, Office of Science. Office of Biological and Environmental Research. Life Sciences Division; National Institutes of Health (United States)
- DOE Contract Number:
- AC03-76SF00098
- OSTI ID:
- 5209469
- Report Number(s):
- LBNL-44570; CODEN: CNREA8
- Journal Information:
- Cancer Research, Vol. 59; ISSN 0008-5472
- Country of Publication:
- United States
- Language:
- English
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