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Abstract
Breast cancer in young patients is known to exhibit more aggressive biological behavior and is associated with a less favorable prognosis than the same disease in older patients, owing in part to an increased incidence of brain metastases. The mechanistic explanations behind these findings remain poorly understood. We recently reported that young mice, in comparison to older mice, developed significantly greater brain metastases in four mouse models of triple-negative and luminal B breast cancer. Here we have performed a quantitative mass spectrometry-based proteomic analysis to identify proteins potentially contributing to age-related disparities in the development of breast cancer brain metastases. Using a mouse hematogenous model of brain-tropic triple-negative breast cancer (MDA-MB-231BR), we harvested subpopulations of tumor metastases, the tumor-adjacent metastatic microenvironment, and uninvolved brain tissues via laser microdissection followed by quantitative proteomic analysis using high resolution mass spectrometry to characterize differentially abundant proteins potentially contributing to age-dependent rates of brain metastasis. Pathway analysis revealed significant alterations in signaling pathways, particularly in the metastatic microenvironment, modulating tumorigenesis, metabolic processes, inflammation, and neuronal signaling. Tenascin C (TNC) was significantly elevated in all laser microdissection (LMD) enriched compartments harvested from young mice relative to older hosts, which was validated and confirmed by immunoblot analysis of whole brain lysates. Additional in vitro studies including migration and wound-healing assays demonstrated TNC as a positive regulator of tumor cell migration. These results provide important new insights regarding microenvironmental factors, including TNC, as mechanisms contributing to the increased brain cancer metastatic phenotype observed in young breast cancer patients.
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1 Women’s Health Integrated Research Center, Inova Women’s Service Line, Inova Health System, Annandale, USA (GRID:grid.414629.c) (ISNI:0000 0004 0401 0871); Uniformed Services University and Walter Reed National Military Medical Center, Gynecologic Cancer Center of Excellence and the Women’s Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Bethesda, USA (GRID:grid.414467.4) (ISNI:0000 0001 0560 6544)
2 National Cancer Institute, Women’s Malignancies Branch, Center for Cancer Research, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075)
3 National Cancer Institute, Women’s Malignancies Branch, Center for Cancer Research, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075); Zymeworks Inc, Vancouver, Canada (GRID:grid.510203.5) (ISNI:0000 0004 4668 6001)
4 Uniformed Services University and Walter Reed National Military Medical Center, Gynecologic Cancer Center of Excellence and the Women’s Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Bethesda, USA (GRID:grid.414467.4) (ISNI:0000 0001 0560 6544); The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, USA (GRID:grid.201075.1) (ISNI:0000 0004 0614 9826)
5 National Cancer Institute, Women’s Malignancies Branch, Center for Cancer Research, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075); Rutgers New Jersey Medical School, Newark, USA (GRID:grid.430387.b) (ISNI:0000 0004 1936 8796)
6 Uniformed Services University and Walter Reed National Military Medical Center, Gynecologic Cancer Center of Excellence and the Women’s Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Bethesda, USA (GRID:grid.414467.4) (ISNI:0000 0001 0560 6544); The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, USA (GRID:grid.201075.1) (ISNI:0000 0004 0614 9826); Uniformed Services University, Department of Surgery, The John P. Murtha Cancer Center Research Program, Bethesda, USA (GRID:grid.265436.0) (ISNI:0000 0001 0421 5525)
7 Women’s Health Integrated Research Center, Inova Women’s Service Line, Inova Health System, Annandale, USA (GRID:grid.414629.c) (ISNI:0000 0004 0401 0871); Uniformed Services University and Walter Reed National Military Medical Center, Gynecologic Cancer Center of Excellence and the Women’s Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Bethesda, USA (GRID:grid.414467.4) (ISNI:0000 0001 0560 6544); Uniformed Services University, Department of Surgery, The John P. Murtha Cancer Center Research Program, Bethesda, USA (GRID:grid.265436.0) (ISNI:0000 0001 0421 5525)