Role of p53 in Irradiated Stroma and Mammary Carcinogenesis
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Ionizing radiation, such as x-rays, is a known human and mouse breast carcinogen. Most studies of radiation-induced cancer emphasize radiation-induced DNA damage in epithelial cells since DNA mutations are believed to initiate carcinogenesis. Non-epithelial breast cells such as the stroma have generally been considered to be silent bystanders during breast cancer. But new concepts emphasizing the central role of tissue environment in maintaining cell function and tissue integrity support the idea that its disruption can contribute to neoplasia. Indeed, it has long been suggested that cancer may be a physiological response to an abnormal environment; our recent studies in irradiated mice support such hypotheses. We know from our own studies that low doses of ionizing radiation alter the composition of tissue microenvironment by rapidly affecting cytokine production and activities, extracellular matrix composition, and the presence of receptors that mediate cell-cell interactions. We found that non-tumorigenic cells transplanted to a radiation exposed mouse mammary gland rapidly formed tumors at a high frequency. This action of radiation on non-target cells to create a cancer-promoting environment is an additional, and understudied, aspect of its cancer causing potential.
 
 
 
 
 
 
 
 We postulate that radiation-induced tissue environment may promote neoplastic behavior by disrupting normal cell functions that are regulated through cell-cell contact, cell-ECM interactions and growth factor signaling. Carcinogen-induced tissue environments do not necessarily induce changes in DNA or in the ability of cells to proliferate. We propose that radiation modifies the interactions between the tissue and cancer-prone cells in a manner that affects the frequency with which previously initiated cells progress to cancer. Disruption of solid tissue interactions is a heretofore unrecognized activity of radiation as a carcinogen, and a novel avenue by which to explore new strategies for intervening during the process in which cancer cells establish their independence from the tissue. In this project we will implement a new model system using mouse mammary epithelial cells in which a known human tumor-suppressor gene, p53, has been deleted in order to study this action of radiation in more detail. These studies will determine whether the action of p53 is specifically involved in producing a preneoplastic population susceptible to promotion by the irradiated stroma.
 
 
 
 
 
 
 
 The significance of this aspect of carcinogenesis lies in recent studies in human cancer that indicate that reestablishing appropriate interactions with the tissue environment can reverse tumorigenesis and neoplastic behavior even in the presence of grossly abnormal genetic damage. Thus we believe that understanding how radiation alters the normal mechanisms by which stroma restrains neoplastic behavior, will provide new strategies for augmenting such mechanisms to prevent cancer and/or reversing this process of deterioration to control cancer.