Overcoming 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. To improve survival there needs to be effective systemic therapy (e.g., adjuvant chemotherapy) used in conjunction with surgical removal of the primary tumor. However, a major reason for failure in treatment is the inherent or acquired drug resistance of the tumor. One of the most exciting recent developments has been the realization that elimination of cancer cells following chemotherapy treatment occurs via the induction of apoptosis, or programmed cell death. This has spurred much interest in what cellular events underlie apoptosis induction and why cancer cells fail to respond to signals (e.g., immune attack, drugs) that would otherwise kill normal cells. 
 
 
 
 
 
 
 
 Interestingly, there appears to be a link between the adhesive events that allow cancer cells to spread in the body and apoptosis. This link is accounted for by a group of cell surface proteins, called integrins, which mediate cell adhesion to extracellular matrix (ECM). Within the past few years, studies by us and others have made it clear that cell-ECM interactions are important in promoting cell survival in a wide variety of cell types. We hypothesized that the local ECM environment of breast cancer cells could provide a survival signal, thereby accounting for their protection from chemotherapy-induced apoptosis. Importantly, we have found that breast cancer cell attachment on some ECM proteins, but not others, provides a remarkable protection for these cells against chemotherapeutic agents. We have also identified the specific integrin molecules that are responsible for the survival signaling in breast cancer cells, and performed initial characterization of the molecular mechanisms as to how integrin signaling interferes with activation of the cell death machinery.
 
 
 
 
 
 
 
 In this project our aim is to further delineate the signaling pathways caused by integrins that contribute to drug resistance; and, importantly, test the translational potential of the project. The key event appears to be the signaling pathway leading from integrin binding to ECM and how this event blocks caspase-8, a critical apoptosis protein, activation in breast cancer cells. This connection is not direct, so we need to locate and understand the intermediates that link integrins and caspase-8. We plan to identify gene targets for integrin signaling that mediate protection against drug-induced apoptosis in breast cancer cells. We will utilize a 'DNA array' approach to detect changes in gene expression that are specifically associated with integrin-mediated protection against drug-induced apoptosis. These studies should provide novel targets for breast cancer treatment. Finally, we will perform initial experiments of anti-integrin compounds as 'chemosensitizers' in a breast tumor model using mice.
 
 
 
 
 
 
 
 We think these could yield novel information on the mechanisms of integrin function and drug resistance. This could have a direct impact on cancer therapy, since anti-adhesive agents are being developed, and if applied correctly, could considerably benefit in the therapy of breast cancer.