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Prolyl Isomerase Function in Breast Cancer
Peptidyl prolyl isomerases (PPI), such as those found in the cyclophilin (Cyp) family significantly contribute to protein folding and structure through their cis-trans conversion of proline imide bonds. Publications from several laboratories have revealed PPIs as critical signaling switches regulating the activity and function of cell surface receptors, kinases, and transcription factors. Recent data from our laboratory have implicated the PPI activity of Cyps in the function of the prolactin/prolactin receptor (PRL/PRLr) complex during the pathogenesis of human breast cancer. In brief, we have demonstrated that Cyp activity regulates both proximal Jak2 kinase and downstream Stat5 transcription factor activity induced by PRL. Given this, we hypothesize that through its regulation of cell surface signaling, including that of the PRLr, Cyp activity substantively contributes to the biology of human breast cancer. This hypothesis has been recently bolstered by our seminal observation that sub-immunosuppressive doses of the PPI inhibitor cyclosporine A (CsA) induce a significant and rapid death of breast cancer cells. To further test our hypothesis of the role of Cyp in breast cancer, this proposal in three aims seeks the following: 1) to examine the mechanistic basis for PRLr-Cyp interaction; 2) to determine if alteration of CypA levels or activity alters PRLr-associated signaling and the breast cancer phenotype; and 3) to assess the effect of CsA treatment on the growth of human breast cancer in an in vivo xenograft model. The proposed studies are highly relevant from both a mechanistic and translational perspective in that they will detail the basis for PRLr-Cyp interaction and function, and directly evaluate the therapeutic potential of CsA against human breast cancer.
Hormones and growth factors stimulate the growth and metastasis of human breast cancer. Their actions are regulated by a family of protein enzymes, termed the cyclophilins (Cyp). Cyp facilitate hormone function by enhancing the signals triggered by hormone binding to receptors on the cell surface. Our lab has recently shown that blockade of the enzymatic activity of Cyp by a drug named Cyclosporine A (CsA) induces the rapid death of human breast cancer cells in a “test-tube”. Given this, we hypothesize that Cyp contribute to the biology of human breast cancer and its progression. This proposal seeks the following: 1) to examine the mechanisms and effects of Cyp interaction with a hormone receptor (the prolactin receptor) on breast cancer cells; 2) to measure the consequences of altering Cyp levels and activity in normal and malignant human breast cells; and 3) to test if CsA can block the growth of breast cancer in mice. The translational potential for this research is high, as CsA has been widely used in transplant patients; however, its use as an anti-cancer agent has never been considered. Therefore, this work is highly relevant in that it will provide new insights into how hormones function through Cyp and directly translate these observations into therapeutic testing of Cyp inhibitors, such as CsA, on breast cancer.