PMID- 37917186 OWN - NLM STAT- Publisher LR - 20231102 IS - 1573-7276 (Electronic) IS - 0262-0898 (Linking) DP - 2023 Nov 2 TI - The murine metastatic microenvironment of experimental brain metastases of breast cancer differs by host age in vivo: a proteomic study. LID - 10.1007/s10585-023-10233-7 [doi] AB - 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. CI - (c) 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Hunt, Allison L AU - Hunt AL AD - Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA, 22042, USA. AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. FAU - Khan, Imran AU - Khan I AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. FAU - Wu, Alex M L AU - Wu AML AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. AD - Zymeworks Inc, Vancouver, BC, V5T 1G4, Canada. FAU - Makohon-Moore, Sasha C AU - Makohon-Moore SC AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Hood, Brian L AU - Hood BL AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Conrads, Kelly A AU - Conrads KA AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Abulez, Tamara AU - Abulez T AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Ogata, Jonathan AU - Ogata J AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Mitchell, Dave AU - Mitchell D AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Gist, Glenn AU - Gist G AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Oliver, Julie AU - Oliver J AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. FAU - Wei, Debbie AU - Wei D AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. FAU - Chung, Monika A AU - Chung MA AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. AD - Rutgers New Jersey Medical School, 185 S Orange Ave, Newark, NJ, 07103, USA. FAU - Rahman, Samiur AU - Rahman S AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. FAU - Bateman, Nicholas W AU - Bateman NW AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. AD - The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA. AD - Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. FAU - Zhang, Wei AU - Zhang W AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. FAU - Conrads, Thomas P AU - Conrads TP AD - Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA, 22042, USA. conrads@whirc.org. AD - Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org. AD - Department of Surgery, The John P. Murtha Cancer Center Research Program, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org. FAU - Steeg, Patricia S AU - Steeg PS AD - Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Building 37, Room 1126, Bethesda, MD, 20892, USA. steegp@mail.nih.gov. LA - eng GR - Intramural Research funding/NH/NIH HHS/United States PT - Journal Article DEP - 20231102 PL - Netherlands TA - Clin Exp Metastasis JT - Clinical & experimental metastasis JID - 8409970 SB - IM OTO - NOTNLM OT - Age OT - Brain metastasis OT - Breast cancer OT - Mass spectrometry OT - Proteomics EDAT- 2023/11/02 18:43 MHDA- 2023/11/02 18:43 CRDT- 2023/11/02 12:04 PHST- 2023/05/25 00:00 [received] PHST- 2023/09/07 00:00 [accepted] PHST- 2023/11/02 18:43 [medline] PHST- 2023/11/02 18:43 [pubmed] PHST- 2023/11/02 12:04 [entrez] AID - 10.1007/s10585-023-10233-7 [pii] AID - 10.1007/s10585-023-10233-7 [doi] PST - aheadofprint SO - Clin Exp Metastasis. 2023 Nov 2. doi: 10.1007/s10585-023-10233-7.