Cell Adhesion and Drug Resistance in Breast Cancer
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 patients with primary breast cancer have disseminated tumors at the time of diagnosis. Thus, surgery alone is not an efficient treatment for most of the patients, and it is imperative that we develop new approaches for effective systemic therapy. Until new, effective systemic therapies are developed we are faced with the use of chemotherapy as an adjuvant treatment. Advances in this area of therapy have been incremental, because of the inherent or acquired drug resistance of the tumor. Thus, chemotherapy in many patients can only delay recurrence, and it often is accompanied by rapid, untreatable progression. The goal of this project is to understand one aspect of drug resistance, which is controlled by the adhesion properties of breast cancer cells.
 
 
 
 
 
 
 
 Recently, we have come to understand that death of cancer cells following different types of chemotherapy occurs via the induction of cell apoptosis, or programmed cell death. Thus, the failure of chemotherapy can be attributed at the cellular level by an acquired resistance to apoptosis. Our approach is to study this process at the level of the cell-extracellular matrix (ECM) interactions mediated by the integrin-family of cell surface receptors. We believe that the local ECM environment of breast cancer cells could provide a survival signal, or block a death signal, thereby accounting for the protection of breast cancer cells from chemotherapy-induced apoptosis.
 
 
 
 
 
 
 
 Our CBCRP-funded project has three inter-related aims. First, we will test the hypothesis that integrin activity provides a protection against drug-induced apoptosis in breast cancer cells in vitro. In these studies, chemotherapeutic drugs will be applied to the cells in the presence and absence of various ECM proteins and the effects on apoptosis will be studied. Second, we will identify and characterize the cellular signaling pathways controlled by integrins that links their function with previously described apoptosis pathways. Drug-induced apoptosis in many cases is mediated via activation of the Fas/Fas-L death pathway, and our working model in these studies, therefore, is that cancer cell attachment to ECM interferes with the Fas/Fas-L system. Finally, we will perform initial experimentation on the potential utility of anti-integrin compounds as chemosensitizers in vivo. In these studies, we will test known anti-integrin agents in a human breast cancer model grown in mice. Such an approach could ultimately reduce the dose of chemotherapeutic compounds lessening their side effects.
 
 
 
 
 
 
 
 Once completed, our pilot studies are anticipated to yield novel information on the mechanisms of integrin function and drug resistance. The studies may have a direct impact on cancer therapy; anti-adhesive agents may have a previously unidentified utility in improving the efficacy of traditional cancer treatment and might provide a considerable benefit in the therapy of breast cancer.