Low-dose radiation-induced senescent stromal fibroblasts render nearby breast cancer cells radioresistant.

In addition to cell cycle arrest, DNA repair or/and apoptosis, ionizing radiation can also induce premature senescence, which could lead to very different biological consequences depending on the cell type. We show in this report that low-dose radiation-induced senescent stromal fibroblasts stimulate proliferation of cocultured breast carcinoma cells. Such effects of senescent fibroblasts appear to result from their ability to induce the expression in carcinoma cells of mitotic genes and subsequent mitotic division. The elevated proliferation of breast carcinoma cells correlates with resistance to radiation as well as to adriamycin. Of interest is the observation that exposure to lower doses (<20 cGy) augments the ability of senescent fibroblasts to promote the survival of cocultured breast carcinoma cells. The resistance appears to be mediated partially by the Akt pathway, because expression of a dominant negative Akt mutant in breast carcinoma cells results in a partial reversal of the radioresistance. The ability of fibroblasts to modulate the radiosensitivity of nearby carcinoma cells implicates the importance of targeting the stroma during therapy.