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Genes that regulate breast cancer brain metastasis
Background: Patients with metastatic breast cancer in extracranial organs often respond to improved treatments, but patients with brain metastases have an extremely poor prognosis. We seek to understand early steps in the establishment of breast cancer brain metastases to help develop new therapies that can prevent breast cancer brain lesions. Objectives/Hypothesis: Our goal is to identify genes that promote tumor cell penetration of the blood brain barrier (BBB). We hypothesize that circulating breast cancer cells capable of colonizing the brain express a unique gene set required for tumor cell entry into the brain microenvironment. Specific Aims: (1) Isolate breast cancer cell populations with a high ("brain-go" cells) or low ("brain-no" cells) potential to cross the blood-brain barrier (BBB) in-vitro and establish brain metastases in-vivo. (2) Identify genes that support transmigration of breast cancer cells through the BBB, using a subtracted cDNA or siRNA library approach. (3) Validate a critical role of identified genes in the establishment of brain metastasis in-vivo after RNAi-mediated gene knock-down and/or gene over-expression. (4) Establish a clinical relevance of identified genes by comparing their expression in patient samples from primary tumors, brain metastases and lesions from other target organs. Study Design: Brain homing variants ("brain-go" cells) and sublines that fail to colonize the brain ("brain-no"cells) will be selected from three new human breast cancer cell models established from circulating tumor cells of breast cancer patients. The cells will be isolated based on their ability to penetrate a barrier of human brain microvascular endothelial cells and astrocytes in a transwell model. Brain metastatic activity will be confirmed in SCID mice by non-invasive bioluminescence imaging and histology. Genes supporting breast cancer cell entry into the brain will be identified by a subtracted cDNA library approach using "brain-go" and "brain-no" cells or an si RNA library approach with in-vivo selected brain homing cell variants. Contributions of candidate genes will be assessed in-vivo after RNAi-based gene knock-down and/or overexpression. The clinical relevance of identified genes will be analyzed in patient samples by real time PCR and immuno-staining to estimate their diagnostic and therapeutic potential. Potential outcomes and benefits of the research: This study will provide information on critical early steps of breast cancer brain metastasis and could directly contribute to the development of targeted therapeutic approaches to prevent breast cancer cell entry into the brain. Brain metastases occur at a late stage and mostly after metastases have been diagnosed in other organs. Thus, timely preventive treatment of patients with progressive breast cancer could eliminate severe complications from brain metastasis and significantly increase survival and quality of life in breast cancer patients.
Breast cancer affects about 12% of women during their lifetime. Most deaths in women with breast cancer are caused by the fact that the cancer can spread from the primary tumor to distant organs including the lungs, liver, bone or even the brain. The process of cancer spreading is called metastasis, and the distant cancer lesions are known as metastases. Metastases that develop in the brain are particularly problematic because there are no therapeutic options that can effectively treat this stage of the disease. While patients with metastases outside the brain often respond well to new and improved treatments, more and more patients are diagnosed with brain metastases but they have a very poor prognosis and only limited options to maintain a decent quality of life. Therefore, our work seeks to understand how brain metastases develop and to provide information on molecular mechanisms that will help develop new therapies to actually prevent breast cancer brain metastases from forming. During the disease, breast cancer cells disseminate from the primary tumor into the blood stream and from there into organs in which they grow and establish metastases. To enter an organ, circulating breast cancer cells need to attach to the blood vessel wall of that particular organ and penetrate the barrier imposed by the vessel wall. The barrier between the blood and the brain, the so-called blood-brain barrier, is much tighter than blood barriers in other organs and consequently much more difficult to penetrate. The specific attributes of breast cancer cells that enable the cells to penetrate the blood brain barrier are largely unknown. Our planned experiments are designed to explore how breast cancer cells enter the brain and to define which attributes of breast cancer cells are critical for this process. Knowledge of these particular early steps in the establishment of brain metastasis would directly contribute to the development of therapeutic approaches that prevent the entry of breast cancer cells into the brain. Brain metastases occur at a late stage in breast cancer patients and mostly after metastases have been diagnosed in other organs. Therefore, timely preventive treatment of patients with progressive breast cancer could eliminate the severe complications from breast cancer brain metastasis and significantly increase the survival rate and quality of life.