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Research Project Description from Lauren Tanabe, PhD, 2014 MCRF Fellow
Project Name: Targeting Matriptase/c-Met Signaling in Inflammatory Breast Cancer
Based on current incidence rates, The National Cancer Institute estimates that about one out of every eight women will be diagnosed with breast cancer at some time during her life. Breast cancer therefore represents a serious public health problem. Inflammatory breast cancer (IBC) is the most aggressive and lethal form of breast cancer with a five-year survival rate of 34% compared to 87% for all other breast cancers combined. IBC is characterized by rapid progression, local and distant metastases, and younger age of onset. The poor prognosis for IBC patients emphasizes the need for new strategies to identify more efficient treatment options. Many breast tumors have elevated levels of proteases, protein-cutting molecules that help the tumor invade tissue and spread to distant sites. Matriptase is a recently discovered enzyme of the protease class that breaks down extracellular protein components, and is located on the surface of the cells that form the ducts of the mammary gland. Matriptase is found at higher levels in most women with breast cancer than in healthy women and a high level of the protease in the breast tumor can predict a more aggressive tumor that is more difficult to treat. Our hypothesis is that matriptase acts as a so-called signaling protease i.e. it promotes breast cancer progression by cutting and thereby activating an important growth factor called Hepatocyte Growth Factor (HGF). When active HGF binds to its receptor (c-Met) on the surface of breast cancer cells, it elicits a variety of pro-cancerous signals that are involved in cancer cell growth, survival and invasion.
In this project, I will test our hypothesis using several different model systems including two human IBC cell lines and a mouse model of IBC. I will study the consequences of eliminating or inhibiting matriptase in cell culture and in IBC cells growing in mice. Importantly, I will also determine the localization of matriptase and c-Met in IBC tumors from patients. This will be possible because of a well-established collaboration with breast cancer clinicians which is very important in order to move basic research towards clinical application. This proposal provides a comprehensive plan for understanding matriptase and its role as a signaling protease in IBC. This information is pivotal in order to identify matriptase as a key player in breast cancer and thus assess the potential clinical benefits from mitigating its activity. In the short term, this study will provide us with knowledge about the role of matriptase in breast cancer, and whether matriptase is a valid candidate target for new therapeutic drug development. Looking ahead, identification of matriptase as a new target and an alternative approach for treating IBC and possible other breast cancer types may provide a new avenue that could benefit patients suffering from this devastating disease.
Summer 2016 Update
Over the course of the last year, we have shown that eliminating or inhibiting matriptase in IBC cells in standard, two-dimensional models and in more complex three-dimensional models (which more closely mimic the tumor micro-environment) effectively silences this pro-cancerous signaling and prevents the hallmarks of tumor cell behavior: cell division and invasion. Importantly, in breast tissue samples from 22 IBC patients, 77% expressed both Matriptase and c-Met, suggesting that this pathway is potentially, a novel therapeutic target for treating IBC.
This new data has been presented at the Membrane-Anchored Serine Proteases Conference (September 2015) and it is currently being prepared for manuscript submission.
Since being awarded the ACS/MCRF grant, I’ve had the pleasure of speaking about our lab’s collaborative research at several ACS fundraising kickoff events and a Making Strides Against Breast Cancer Pacesetters recognition event at Ford Field to staff. I also spoke briefly with FOX2 News Detroit about the symptoms of IBC at the 2015 Making Strides Against Breast Cancer Walk in Hart Plaza. Being able to convey our research to such captivating audiences and bring awareness to others about a devastating disease, that is often misdiagnosed, helps to motivate my team and me to continue our vital work.
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