FKBP Proteins as Molecular Targets in Breast Cancer Therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Many sophisticated technologies now routinely identify abnormal patterns of gene products that correlate with the degree of malignancy in breast cancer patients. However, to date, it is not known which of these genes actually cause, and not just correlate with, the spreading of breast cancer. Recently we have become interested in a diverse group of proteins, called FKBPs. The FKBPs bind to FK506, which is a fungal anti-bacterial drug used in medicine as an immunosuppressant to prevent rejection of organs following transplantation. FKBPs are also known to participate in many cellular processes such as cell signaling, protein transport and transcription. We and others have found that there are lower amounts of the gene product from one of the FKBP family, called the FKBPr38 gene, in two of the more aggressive mouse cancer cell lines derived from different tissue origins. In addition, we have also demonstrated that FKBPr38, as well as FKBP12 (a highly similar gene product to FKBPr38) reduce breast cancer spread in mice. We found that these FKBP genes can also reduce the ability of cultured human breast cancer cells to invade, potentially by influencing other genes (effectors) that are highly relevant to the invasion/metastatic potential of breast cancer cells. 
 
 
 
 
 
 
 
 In this project we propose to extend these results obtained from the mouse model into human xenograft model (i.e, human breast cancers grown in mice) that recapitulates progression of human breast cancer invasion and metastasis. The questions we are asking are: (1) how widespread the abnormal FKBP gene expressions are among human breast cancer patients; (2) are FKBP genes functionally involved in the invasion/metastasis of human breast cancer; (3) what are the "down-stream effectors" that are responsible for the anti-tumor effects of FKBP genes, and (4) can FKBP pathways and targets be a new breast cancer therapy strategy? To address these questions, we will first document how widespread lower amounts of FKBPr38 and FKBP 12 gene products are in aggressive human breast cancer cells and in primary human breast tumor biopsies. We will determine how FKBPr38 and FKBP12 abnormalities affect the behaviors of human breast cancer cells in culture and in animals, including their growth patterns, their abilities to survive under stress, to stimulate new blood vessel formation, and to invade normal tissues which eventually lead to the spread of breast cancer. Lastly, we will test whether FKBP genes and their effectors, when administered alone or in combination, can produce comparable, additive, or synergistic effects against breast tumors grown in mice. The molecular techniques we will use in these studies ranges from Western blot protein analysis and immunohistochemistry, RT-PCR, and gene transfer (cell transfections) using cDNAs and inhibitory ribozymes. We think that an important target of FKBP anti-tumor activity is the invasive metalloproteinase, MMP-9. We will test whether MMP-9 expression is affected in our studies and whether lower MMP-9 expression can account for reduced breast cancer cell invasive properties. In a similar manner, we will test whether the anti-invasive protein, syndecan-1, is also influenced by FKBPs. 
 
 
 
 
 
 
 
 These studies should help to better understand what causes and promotes or inhibits the metastatic spread of human breast cancers, as well as to provide an additional genetic basis for developing more effective treatments for human patients with breast cancer.