Role of Adrenomedullin in Breast Cancer Bone Metastasis and Chemoresistance

Abstract

Abstract : The majority of patients with advanced breast cancer develop bone metastases, which are incurable. Recently, tumor-secreted factors have shown promise as targets for the treatment of bone metastasis. Adrenomedullin (AM) is a breast cancer-secreted peptide that is pro-proliferative, anti-apoptotic, pro-angiogenic, and stimulates new bone formation. AM overexpression increases bone metastases while AM knockdown decreases bone metastases in mouse models of prostate and lung cancer respectively. The objective of this project is to validate AM as an important target for the treatment of breast cancer bone metastasis. I hypothesize that AM expression increases bone metastases and resistance to chemotherapy. Specific Aims: (1) To determine if AM expression by breast cancer cells increases bone lesion formation in bone metastasis mouse models. (2) To determine the role of AM in breast cancer cells. Key Research Accomplishments: (1) MDA-MB-231 clones that overexpress AM were produced. (2) Stable AM shRNA knockdown MDA-MB-231 breast cancer cell clones were produced. (3) Decreasing AM in breast cancer cells increased bone lesion formation but decreased mammary fat pad tumor-take and growth in mice. Relevance: Currently no treatments improve overall survival for breast cancer bone metastasis patients. Inhibitors of certain tumor-secreted factors have decreased bone metastases in mice. My results indicate that inhibitors of the tumor-secreted factor AM would not be a good treatment for breast cancer bone metastases.