Does Cell Aging Cause Breast Cancer?

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Judith Campisi, Ph.D. -
Award Cycle: 1997 (Cycle III) Grant #: 3IB-0036 Award: $239,303
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1997)
The single largest risk for developing cancer is age. The exponential rise in cancer incidence with age has been explained by the accumulation of a critical number of mutations, primarily in the epithelial cells that give rise to the majority of malignant tumors in adults. However, it is unlikely that mutation accumulation completely accounts for cancer. Recently, epigenetic factors, such as the microenvironment, have become appreciated as contributors to cancer.

Little is known at the molecular level about the role of cellular aging in breast cancer. We propose that aging changes the breast epithelial cell microenvironment and contributes to cancer. Further, the age-dependent environmental changes may act in synergy with genetic mutations. We propose to study ‘replicative senescence’, which is the fixed number of cell divisions that a cell type is capable of in the body. This type of aging limits cell division by imposing an irreversible block to cell cycle progression. Interestingly, ‘replicative senescence’ also causes cells to become resistant to apoptotic (programmed) cell death. Recently, we provided the first evidence that senescent cells exist and accumulate with age. Our preliminary data suggest that senescent human fibroblasts express activities that can ‘relax’ the environmental control on breast epithelial cells. For example, senescent fibroblasts secrete extracellular matrix-degrading enzymes and epithelial cell growth factors. These factors could stimulate the growth and/or other malignant properties of neighboring breast epithelial cells.

We plan to study the role of senescent fibroblasts in mediating the transformation of breast epithelial cells in culture. Human fibroblasts from breast and non-breast origins will be co-cultured with murine and human breast epithelial cells having different potentials for growth, migration and invasion. We will use both monolayer-type (one cell layer thick) cultures and three-dimensional cultures containing various extracellular components. We will measure epithelial cell growth, differentiation, cell-cell and cell-extracellular matrix interactions, cell migration and invasiveness. Further, in other experiments we plan to relate senescence in fibroblasts to breast epithelial cells in which we insert either normal or mutated genes associated with breast cancer. We will explore the feasibility of inhibiting the "pro-carcinogenic" activities of senescent fibroblasts.

These experiments will provide a molecular framework for understanding the role of cellular aging in breast cancer. Future treatment of breast cancer may focus on counteracting these senescent changes in the microenvironment as an alternative to directly targeting the cancer cells

Final Report (2000)
Note: This grant was extended one year to complete the aims.

We have studied the role of cell aging in breast cancer using three cell culture systems and an animal model. The general design of our studies was to co-culture pre-cancerous cells with either normal non-senescent or normal senescent (i.e., aging) cells, and determine whether the growth of the pre-cancerous cells was altered by the presence of the normal cells. The pre-cancerous cells we tested were cell lines derived from human breast epithelium (S1), mouse breast epithelium (SCp2) or human epidermis (skin) (HaCAT). S1, SCp2 and HaCAT cells are all non-tumorigenic epithelial cells that carry mutations that predispose them to transforming into cancer cells. The pre-senescent and senescent normal cells were human fibroblasts, cells that typically synthesize the stroma or extracellular matrix support system for breast or skin epithelial cells. We found that all three epithelial cell lines were stimulated to proliferate by the presence of senescent, but not non-senescent, fibroblasts. This growth stimulation was due in large measure to molecules that were secreted by the senescent cells. Moreover, when HaCAT cells were injected into mice together with either non-senescent or senescent fibroblasts, the cells co-injected with senescent fibroblasts were stimulated to form tumors.

These findings support our hypothesis that senescent cells can stimulate the appearance of late life cancers, including breast cancer. In addition, the data supports the idea that the ability of senescent cells to stimulate tumor formation is due to the secretion of growth-promoting molecules. In future studies, we plan to identify the secreted molecules that are important for this effect, and to develop strategies to prevent their secretion or neutralize their growth stimulatory effects.

Our studies provide a new potential target for preventing or controlling the progression of breast cancer-- namely, the expression and secretion of growth stimulatory molecules by senescent stromal cells.