Abstract
Simple SummaryToo many women still die of breast cancer each year. Those breast cancers that kill are those with cells that have migrated away from the primary tumor in the breast and established new tumors at other sites in the body. These tumors are not reached when the original tumor in the breast is removed. This study was designed to determine why some breast cancers move away from their primary tumor and others do not. We have identified a protein that inhibits this movement. Understanding this finding may provide us with ways to inhibit tumor cell movement in patients.Breast cancer is the most common cancer in women. Despite advances in early detection and treatment, it is predicted that over 43,000 women will die of breast cancer in 2021. To lower this number, more information about the molecular players in breast cancer are needed. Guanylate-Binding Protein-2 has been correlated with better prognosis in breast cancer. In this study, we asked if the expression of GBP-2 in breast cancer merely provided a biomarker for improved prognosis or whether it actually contributed to improving outcome. To answer this, the 4T1 model of murine breast cancer was used. 4T1 cells themselves are highly aggressive and highly metastatic, while 67NR cells, isolated from the same tumor, do not leave the primary site. The expression of GBP-2 was examined in the two cell lines and found to be inversely correlated with aggressiveness/metastasis. Proliferation, migration, and invadosome formation were analyzed after altering the expression levels of GBP-2. Our experiments show that GBP-2 does not alter the proliferation of these cells but inhibits migration and invadosome formation downstream of regulation of Rho GTPases. Together these data demonstrate that GBP-2 is responsible for cell autonomous activities that make breast cancer cells less aggressive.
Highlights
Breast cancer strikes 1 in 8 women in the U.S, or about 12.3% of women [1]
We show that murine ortholog of GBP-2 (mGBP-2) correlates with better prognosis in this model system and contributes to better outcome not by inhibiting cell proliferation but by significantly inhibiting cell migration and invadosome formation, as the consequence of or coincident with activating CDC42 and RhoA and inhibiting the activation of Rac1
Where the expression of Human GBP-1 (hGBP-1) is part of a gene signature that correlates with improved prognosis of human breast cancers, hGBP-1 is expressed in both tumor cells and the surrounding stroma [6]
Summary
Breast cancer strikes 1 in 8 women in the U.S, or about 12.3% of women [1]. It is estimated that over 281,000 cases of breast cancer were diagnosed in women and over43,000 women will die of the disease in 2021 [2]. Breast cancer strikes 1 in 8 women in the U.S, or about 12.3% of women [1]. It is estimated that over 281,000 cases of breast cancer were diagnosed in women and over. Breast cancer remains the most common cancer in women and the second most deadly [2]. While significant improvements have been achieved in early detection and the treatment of some types of breast cancer, as the numbers of older Americans increase so does the number of women with breast cancer. While the biomarkers and clinical targets in breast cancer have expanded, there are still some types of breast cancer, such as triple-negative breast cancer (TNBC), that lack targeted therapies and are short on biomarkers. We need more biomarkers to predict clinical outcomes and additional targets to improve therapy
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