| Endocrine therapy has proven a valuable approach to the treatment of breast cancer. In particular, antiestrogens have demonstrated significant improvement in survival rates, and have recently been shown to prevent breast cancer development in women in high-risk populations. Other endocrine or cytokine-based therapies, including glucocorticoids and interferons, which have been highly effective as adjuvant treatment of hematological cancers, have also shown promise in breast cancer. However, due to the less consistent clinical responses to both glucocorticoids and interferons in breast cancer patients, research efforts have continued to focus on improving their efficiency.;Important recent insights into the underlying molecular biology of hormone signal transduction have identified the critical involvement of cytoplasmic STAT transcription factors. These molecular intermediaries convey the signal from the cell surface to the nucleus where they activate transcription of target genes. One hormone, which signals via the STAT pathway, is of particular relevance in breast cancer: namely, the mammary growth and differentiation factor, prolactin.;The specific aims of this study were: (1) to examine whether the glucocorticoid, dexamethasone, may promote the terminal differentiation of breast cancer cells by stimulating prolactin activation of the transcription factors, STAT5a and STAT5b; (2) to examine whether prolactin interferes with type I interferon signal transduction by competing for limited cytoplasmic STAT factors, thus antagonizing the antiproliferative effect of type I interferons in breast cancer treatment; and (3) to test if mammary tumor cell lines, like many hematopoietic cancer cells, become sensitized to the antiproliferative effect of type I interferons by pretreatment with interferon-gamma.;After establishing differentiation conditions in breast cancer cells, STAT transcription factor expression, activation and DNA-binding were examined by immunoblot and electrophoretic mobility shift assay. Based on the research work presented in this thesis, we conclude that: (1) Glucocorticoids have a profound positive effect on prolactin signal transduction by STAT5 transcription factors in some, but not all breast cancer cells. STAT5a expression is clearly linked to differentiation of breast cancer cells, and our findings may have important implications for the use of glucocorticoids in differentiation therapy of select breast cancer patients. (2) Prolactin activates STAT1 but does not disrupt STAT1-STAT2 heterodimer formation or the antiproliferative effect of type I interferons in human breast cancer cells. In fact, cytoplasmic levels of STAT1 are not rate-limiting, and prolactin and type I interferons maintain an unexpectedly high degree of signal fidelity in human breast cancer cell lines despite activating overlapping sets of STAT transcription factors. (3) Pretreatment of mammary cancer cells with interferon-gamma enhanced signal transduction and antiproliferative effect of type I interferons (alpha/beta), a finding that may lead to improved interferon-based therapy of breast cancer patients. |
