Role of Cell Senescence in Breast Cancer
Annual rept. 1 Aug 1999-31 Jul 2000
CALIFORNIA UNIV BERKELEY
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Cancer incidence rises exponentially with age. This project tests the hypothesis that cellular senescence of stromal fibroblasts contributes to the age-dependent increase in breast cancer by creating a more permissive environment for the expression of malignant phenotypes by breast epithelial cells. Here, we report that both mouse and human immortal pre-malignant breast epithelial cell lines increase 2 to 5 times their proliferation in the presence of senescent, compared to presenescent, human fibroblasts. Both soluble and insoluble secreted factors contribute to senescent fibroblasts effect on epithelial cell proliferation. The effect of senescent fibroblasts on breast epithelial cell proliferation is observable even when they are present as only 10 of a mixed population of presenescent and senescent fibroblasts. In addition, fibroblasts induced to undergo premature senescence by oncogenic ras or p14ARF expression stimulate epithelial cell proliferation in a manner similar to that observed with replicatively senescent fibroblasts. Most importantly, when senescent fibroblasts are co-injected into nude mice together with nontumorigenic epithelial cell lines, they stimulate tumorigenesis resulting in a higher frequency of tumors and larger tumor size relative to controls co-injected with presenescent fibroblasts. Taken together, these results support our hypothesis that cellular senescence of stromal fibroblasts may contribute to breast tumorigenesis.
- Anatomy and Physiology
- Medicine and Medical Research