Predicting Response: Identifying Molecular Determinants Of Endocrine Response And Resistance In Breast Cancer

Blocking estrogen activity or production through the use of anti-estrogens such as tamoxifen and aromatase inhibitors, respectively, has had a significant impact on improving the survival of breast cancer patients. However, innate or acquired resistance to these endocrine therapies remains a major clinical problem and a challenge to the successful treatment of this disease. A recent article explored the role of the tumor-suppressor gene TP53 in the response of breast cancer cell lines to tamoxifen and the pure anti-estrogen, fulvestrant. Mutations in TP53, which occur frequently in breast cancer like many other types of neoplasia, are already known to negatively influence prognosis, but here their role in the response to anti-estrogen treatment was evaluated. This study found that cells harboring p53 mutations were more resistant to the cytotoxic effects of 4-hydroxytamoxifen than their p53 wild-type counterparts. Furthermore, mutant p53 cells were actually stimulated by low concentrations of 4-hydroxytamoxifen, with evidence that this may be mediated through enhanced growth factor signaling. By contrast, p53 status did not affect the response to fulvestrant. This article further delineates the role of p53 as a determinant of the endocrine response.