Date Published: May 5, 2009
Publisher: Public Library of Science
Author(s): Senthil K. Muthuswamy
Abstract: Senthil Muthuswamy discusses a study that characterizes a new tumor suppressor gene, ductal epithelium-associated RING Chromosome 1, that is frequently inactivated in breast cancer.
Partial Text: Pathologists use loss of normal tissue architecture as a key criterion to identify and categorize disease states. Epithelia in all glandular structures in vivo have a characteristic organization where they line a central lumen and are involved in absorptive and/or secretory functions. Under some physiological conditions—such as pregnancy, wound healing, and the periodic tissue remodeling that occurs in tissues such as colon—there is a significant increase in the rate of cell proliferation. Although the proliferation rate in these physiological conditions is higher than that seen under disease states, the overall tissue size and structure are maintained. Such maintenance of size/structure occurs because the increased proliferation is tightly coupled with tissue morphogenesis programs, resulting in remodeling of normal tissue architecture.
In this issue of PLoS Medicine, Ann Killary and colleagues describe the discovery and characterization of a new tumor suppressor gene, ductal epithelium–associated RING Chromosome 1 (DEAR1) , that maps to Chromosome 1p35.1, a region of the chromosome that is associated with loss of heterozygosity in breast and other epithelial cancers . The authors also demonstrate that DEAR1 is mutated in 13% of primary human breast cancers. Thus DEAR1 is a frequently inactivated gene in breast cancer.
Ann Killary and colleagues show that DEAR1 is expressed in the ductal and glandular epithelia of many adult tissues, including breast, bladder, kidney, prostate, pancreas, and salivary gland. While normal breast epithelia express high levels of DEAR1, the authors found that 70% of ductal carcinoma in situ (DCIS) specimens showed a loss or down-regulation of DEAR1 expression. Such loss or down-regulation suggests a role for DEAR1 during early stages of breast cancer. Consistent with this possible role, the researchers observed a mutation that changes arginine at position 187 to glutamine (R187Q) in both breast tumor and adjacent normal epithelia. This mutation was never seen in normal individuals or in the single nucleotide polymorphism database, suggesting that mutation of DEAR1 may be an early event that occurs during the initial stages of transformation of normal epithelia.
When cultured on a bed of extracellular matrix (such as Matrigel), normal mammary epithelial cells form three-dimensional acini-like structures with a layer of polarized epithelial cells surrounding a central hollow lumen. In Killary and colleagues’ study, down-regulation of DEAR1 in normal mammary epithelial cells resulted in formation of aberrant acinar structures with decreased rates of apoptosis and a loss of normal cell polarity. Down-regulation of DEAR1 did not have any effect on proliferation of these normal mammary epithelial cells, showing that DEAR1 regulates cell architecture pathways independent of any effect on cell proliferation.
DEAR1 maps close to another tumor suppressor, CHD5, which was recently mapped to Chromosome 1q by a chromosome engineering approach . With the identification of DEAR1 we are beginning to develop a deeper understanding of the molecular basis for the loss of Chromosome 1q in human cancers. While CHD5 regulates cell proliferation pathways by increasing expression of the cell cycle inhibitor p16/ink4a locus, DEAR1 regulates cell architecture. It is possible that CHD5 and DEAR1 represent the two sides of the transformation process, where loss of CHD5 results in aberrant proliferation while loss of DEAR1 results in loss of tissue architecture, and the combination of the events can drive changes in the epithelial tissues that can progress towards cancerous growth. It would be interesting to determine the effect of combined loss of CHD5 and DEAR1 both for clinical prognosis and during transformation of epithelial cells in culture and animal models.