When cancer treatments such as chemotherapy or hormonal therapy fail to cause tumor regression, the cause is often a malfunction of a natural pathway called apoptosis, which breaks down cells in the body. Many breast cancer cells require estrogen for survival (called estrogen receptor–positive breast cancers), and apoptosis of such cells can be induced with treatments that block estrogen, such as tamoxifen, fulvestrant, or aromatase inhibitors. Paradoxically, some cells can become adapted to survive when deprived of estrogen and undergo apoptosis in the presence of estradiol. However, the mechanism by which estrogen promotes apoptosis is not well understood.
To try to understand how the estrogen estradiol induces apoptosis in cells, V. Craig Jordan, Ph.D., D.Sc., of the Fox Chase Cancer Center in Philadelphia, and colleagues developed a line of breast cancer cells, called MCF-7:5C, that are resistant to estrogen withdrawal and that undergo apoptosis when treated with very small concentrations of estradiol. The researchers treated MCF-7:5C cells with estradiol and fulvestrant, and they also injected the cancer cells into mice to study estradiol's influence on apoptosis in tumors.
They found that estradiol induces apoptosis by activating the so-called intrinsic apoptotic pathway. This pathway is controlled by proteins on the membrane of cell organelles called mitochondria. Estradiol increased the expression of several proteins on the membrane of cell mitochondria, led to depolarization of the mitochondrial membrane, and stimulated the release of a molecule called cytochrome c int o the cell's interior, where it could activate several cellular enzymes, called caspases, which in turn initiate cell degradation. They also found that estradiol caused complete tumor regression in mice that had been injected with the MCF-7:5C breast cancer cells.
"These laboratory data have important clinical implications, particularly for the use of aromatase inhibitors as long-term therapy," write the authors, "and they suggest that, if and when resistance to aromatase inhibition occurs, a strategy of treatment with estrogen ?may be sufficient to kill the cancer and control disease progression."