Emilly S Villodre1,2, Xiaoding Hu1,2, Bedrich L Eckhardt1,2,3, Richard Larson2,4, Lei Huo2,5, Ester C Yoon5, Yun Gong2,5, Juhee Song6, Shuying Liu1, Naoto T Ueno1,2, Savitri Krishnamurthy2,5, Stefan Pusch7,8, Debu Tripathy1,2, Wendy A Woodward2,4, Bisrat G Debeb1,2. 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia. 4. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 7. German Cancer Consortium Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany. 8. Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.
Abstract
BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive. METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariable Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided. RESULTS: We generated new sublines that exhibited a distinct propensity to metastasize to the brain. NDRG1-high-expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher's exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [95% CI] = 1.20 to 4.29, P = .009) and breast cancer-specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17, 95% CI = 1.10 to 4.30, P = .03) and breast cancer-specific survival rates (HR = 2.27, 95% CI = 1.05 to 4.92, P = .04). CONCLUSIONS: We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.
BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive. METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariable Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided. RESULTS: We generated new sublines that exhibited a distinct propensity to metastasize to the brain. NDRG1-high-expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher's exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [95% CI] = 1.20 to 4.29, P = .009) and breast cancer-specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17, 95% CI = 1.10 to 4.30, P = .03) and breast cancer-specific survival rates (HR = 2.27, 95% CI = 1.05 to 4.92, P = .04). CONCLUSIONS: We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.
Authors: Maria Aparecida Nagai; Renê Gerhard; José Humberto T G Fregnani; Suely Nonogaki; Regina Barbosa Rierger; Mário Mourão Netto; Fernando A Soares Journal: Breast Cancer Res Treat Date: 2010-04-06 Impact factor: 4.872
Authors: Daniel L Smith; Bisrat G Debeb; Parmeswaran Diagaradjane; Richard Larson; Swaminathan Kumar; Jing Ning; Lara Lacerda; Li Li; Wendy A Woodward Journal: Genes Cancer Date: 2021-03-13
Authors: Kazutaka Fukumura; Prit Benny Malgulwar; Grant M Fischer; Xiaoding Hu; Xizeng Mao; Xingzhi Song; Sharia D Hernandez; Xiang H-F Zhang; Jianhua Zhang; Edwin Roger Parra; Dihua Yu; Bisrat G Debeb; Michael A Davies; Jason T Huse Journal: Acta Neuropathol Date: 2021-01-04 Impact factor: 17.088
Authors: Asad Ur Rehman; Parvez Khan; Shailendra Kumar Maurya; Jawed A Siddiqui; Juan A Santamaria-Barria; Surinder K Batra; Mohd Wasim Nasser Journal: Mol Cancer Date: 2022-05-10 Impact factor: 41.444