IGF-II and cathespin D in tumor growth and metastasis
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 women die as a result of metastasis, the process by which tumor cells dissociate from the initial tumor and establish a new tumor at a different site. Currently, the most valuable predictor of breast tumor metastasis is the presence of cancer cells in lymph nodes. Nevertheless, new tumors reappear in 30% of patents with no cancer cells in the lymph nodes. Thus, more accurate prognostic indicators are needed. Our project is designed to investigate the basic biology of how three proteins interact (IGF-II, IGF-II receptor and cathepsin D) in breast cancer tumor growth and metastasis. Our proposal is relevant to the understanding of breast cancer development and metastasis, the major cause of death in breast cancer patients and an important BCRP priority area.
 
 
 
 
 
 
 
 Cathepsin D appears to be a protein involved in metastasis. Several studies in breast cancer patients have demonstrated that high levels of cathepsin D correlated with significantly reduced cancer- free intervals after treatment. When studied by "immunocytochemistry" (the standard clinical laboratory assay) the correlation of cathepsin D and metastases have provided conflicting evidence. Thus, further studies with more precise assays for cathepsin D activity are necessary. Preliminary results suggest that high levels of "active" cathepsin D in breast tumors are associated with the risk of metastasis. 
 
 
 
 
 
 
 
 The present study seeks to validate this observation. IGF-II is a protein that stimulates cell growth and cathepsin D production. Both IGF-II and cathepsin D are secreted by breast cancer tumors and bind the IGF-II receptor. Despite distinct binding sites, IGF-II binding can affect cathepsin D binding to the IGF-II receptor. Thus, we believe that increased concentrations of IGF-II compete with cathepsin D for the IGF-II receptor; to restore the balance, increased secretion of cathepsin D occurs. We developed a breast cancer cell system that confirmed the theory and demonstrated how IGF-II blocked the transport of cathepsin D, increasing its secretion.
 
 
 
 
 
 
 
 In summary, this proposal is designed to demonstrate that interactions between IGF-II and cathepsin D with the IGF-II receptors increase cathepsin D secretion, resulting in tumor growth and metastasis. To test this, we will determine whether: (1) IGF-II expression/cathepsin D secretion increases tumor growth and metastasis; and (2) Higher levels of specific forms of cathepsin D and IGF-II are found in breast tumor tissues than in normal breast tissues and are associated with metastasis. Expression of IGF-II and cathepsin D in paired normal and tumor tissue from breast cancer patients will be studied. Elucidation of the regulatory mechanism(s) in which these proteins participate and their interactions with factors contributing to the progression of breast cancer may have direct applications for improvements in patient treatment and follow-up.