Determining How Down Regulating Sirtuin 1 Expression in Breast Cancer Generates a Secretome that Promotes Invasion and Metastasis

Fellow: Arash Latifkar

Mentor: Richard Cerione

Department of Molecular Medicine
Sponsor: Breast Cancer Coalition of Rochester (BCCR)
Title: Determining How Down Regulating Sirtuin 1 Expression in Breast Cancer Generates a Secretome that Promotes Invasion and Metastasis
Project Amount: $25,000
Project Period: April 2018 to March 2019

DESCRIPTION (provided by applicant): 

Aggressive metastatic breast cancer is responsible for the deaths of more than 40,000 people per year in the U.S., despite the best efforts of researchers and clinical oncologists. The disappointing outcomes associated with a number of treatment strategies designed to prevent breast tumor growth and metastatic spread show that we still have a long way to go toward devising better strategies to block these events. However, an important development in the field of cancer research could offer exciting new possibilities toward achieving beneficial clinical results against the more aggressive cases of breast cancer. This has to do with the ability of aggressive breast cancer cells to generate a specific class of secretory vesicles, referred to as exosomes. These vesicles function as “satellites of communication”, as they are shed from “donor” cancer cells and travel to secondary sites, making these sites highly receptive to metastatic spread. Recently, I made an exciting discovery regarding how breast cancer cells might be ‘primed’ to become invasive, an early step in the metastatic process. Specifically, I have established a novel connection between the reduced expression of a protein called Sirtuin 1 (SIRT1) in breast cancer cells and the functional impairment of a key intracellular organelle (called the lysosome), which results in a marked increase in the number of exosomes produced and shed by the SIRT1-depleted cells. I further discovered that these exosomes contain unique cargo that greatly enhances metastatic potential. Moreover, I found that breast cancer cells with low levels of SIRT1 also secrete enzymes that enable cells to break free from their primary sites and enter the blood stream to spread to new sites and undergo metastasis. Armed with this new information, I will set out to further characterize what I believe to be novel insights into the underlying mechanisms of metastatic breast cancer.The expectation is that from the results of these studies, new strategies will emerge that will help to defeat this devastating disease.