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Background: Obesity, the modern ‘epidemic’, has shared correlation with fatty liver disease and breast cancer. However, previous studies on the relation between fatty liver and breast cancer have shown conflicting results on the impact of fatty liver on the survival and recurrence of breast cancer patients. And there was no attempt to find out the effect of liver fibrosis, which is the consequence of fatty liver disease, on female breast cancer patients. So we attempted to investigate the prognostic value of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis(NASH)-related liver fibrosis in patients with breast cancer undergoing surgery, using noninvasive tools like liver-to-spleen attenuation(L/S) ratio and Fibrosis-4(FIB-4) score, respectively. Methods: A total of 933 patients diagnosed with primary invasive breast cancer and receiving surgery at the university-affiliated referral center between April 2006 and December 2019 were included. After excluding patients who had significant alcohol consumption and hepatitis viral infection,838 patients were divided into two groups according to the L/S ratio of 1 measured by the preoperative low-dose computed tomography: 91 patients(10.9%) with a L/S ratio< 1 vs 747 patients(89.1%) with a L/S ratio≥1. They were also divided into two groups based on the FIB-4 score of 2.67: 804 patients (95.9%) with a FIB-4 score< 2.67 vs 34 patients (4.1%) with a FIB-4 score≥2.67. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI). Results: Patients with NAFLD were older, had higher BMI, and had a higher proportion of mastectomy and hyper-transaminasemia. They showed worse overall, disease-free, and regional recurrence-free survivals compared to those without NAFLD (p=0.008, 0.043, and 0.017, respectively), but no significant differences in local recurrence-free, systemic recurrence-free, and contralateral breast cancer-free survivals. The survival outcome of breast cancer did not show any relationship with NASH-related liver fibrosis (overall survival; p=0.061, disease-free survival; p=0.557). NAFLD was a significant risk factor for mortality in multivariable analysis (HR, 2.077; 95% CI, 1.052–4.102; p=0.035). After stratifying for subtypes of breast cancer, the L/S ratio remained a significant predictor of overall, disease-free, local recurrence-free, and regional recurrence-free survivals in only the hormone receptor-positive/HER2−negative subtype (p=0.007, 0.005, 0.009, and < 0.001, respectively). Conclusion: NAFLD is significantly associated with decreased overall survival, disease-free survival and increased regional recurrence in patients with breast cancer especially the hormone receptor-positive/HER2−negative subtype. NASH-related fibrosis was not associated with survival. Therefore, NAFLD should be assessed in the preoperative setting for predicting long-term prognoses of breast cancer patients Citation Format: Hyunsu Yeoh, Siwon Jang, Jong-Ho Cheun, Jin Ah Kwon, Myoung Seok Lee, Bumjo Oh, In Sil Choi, Sohee Oh, Jongjin Kim, Jeong Hwan Park, Won Kim, Ki-Tae Hwang. Prognostic impact of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis-related liver fibrosis on postoperative long-term outcomes of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-06.

Intratumoral genetic heterogeneity leads to tumor progression and therapeutic resistance. However, due to the difficulty associated with its assessment, application of intratumoral genetic heterogeneity as a prognostic or predictive marker is limited. We investigated the significance of Shannon diversity index as a tool for measuring genetic heterogeneity by performing fluorescence in situ hybridization of c-Myc gene in invasive breast cancers, and correlated the Shannon diversity index for c-Myc copy number variation with clinicopathologic features of tumor including patient survival. Shannon index for c-Myc copy number variation strongly correlated with average c-Myc copy number and was significantly higher in tumors with c-Myc genetic or regional heterogeneity than in those without c-Myc amplification. High Shannon index was associated with high histologic grade, lymphovascular invasion, p53 overexpression, high Ki-67 proliferation index, hormone receptor negativity, and HER2 amplification. In survival analyses, c-Myc amplification or c-Myc copy number gain was not associated with patient survival. However, a high level of Shannon index was associated with poor disease-free survival. In subgroup analyses, it was found to be an adverse prognostic factor in hormone receptor-positive group, but not in hormone receptor-negative group. In a validation set, high Shannon diversity index for c-Myc copy number variation was also found to be associated with poor survival of the patients. We further investigated the correlation with clinicopathologic features and predictive power of Shannon index using another gene, fibroblast growth factor receptor 1 (FGFR1) and observed that high Shannon index for FGFR1 gene copy number variation was an independent prognostic factor for poor clinical outcome in a whole group and in hormone receptor-positive subgroup. In conclusion, this study demonstrated that higher diversity index was associated with adverse pathologic parameters of breast cancer and poor clinical outcome suggesting that Shannon diversity index, which represents intratumoral genetic heterogeneity, can be used as a potential biomarker for tumor progression and prognostication in patients with breast cancer. Citation Format: Yul Ri Chung, Hyun Jeong Kim, Young A Kim, Mee Soo Chang, Ki-Tae Hwang, So Yeon Park. Diversity index as a novel predictor of tumor progression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3937. doi:10.1158/1538-7445.AM2017-3937

Metastatic spread is the major cause of death from breast cancer. We previously showed that H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells, while both H-Ras and N-Ras induce proliferation/transformation. Here, we identified flotillin-1 as an H-Ras-induced lipid raft protein through comparative proteome profiling of lipid raft proteins. Flotillin-1 interacts with H-Ras in lipid raft at a higher affinity than with N-Ras. Small interfering RNA(siRNA)-mediated flotillin-1 knockdown significantly reduced H-Ras activation and H-Ras-mediated motility/invasion in MCF10A cells engineered to express active H-Ras as well as in Hs578T breast carcinoma and T24 bladder carcinoma cells that express endogenous active mutant of H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program. Flotillin-1 was crucial for the activation of the Ras-GRF1 exchange factor and its interaction with H-Ras in lipid rafts. Using a xenograft tumor model, we show that knockdown of flotillin-1 reduces the tumor growth in vivo. Importantly, tissue microarrays of 289 breast cancer patients revealed that flotillin-1 expression in the plasma membrane positively correlates with HER2/neu expression(p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4165. doi:1538-7445.AM2012-4165

Metastatic spread is the major cause of death from breast cancer. We previously showed that H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells, while both H-Ras and N-Ras induce proliferation/transformation. Here, we identified flotillin-1 as an H-Ras-induced lipid raft protein through comparative proteome profiling of lipid raft proteins. Flotillin-1 interacts with H-Ras in lipid raft at a higher affinity than with N-Ras, elucidating a molecular nature of the crucial link between lipid rafts and the function of H-Ras. Small interfering RNA (siRNA)-mediated flotillin-1 knockdown significantly reduced H-Ras activation and H-Ras-mediated motility/invasion in MCF10A cells engineered to express H-Ras and in highly invasive human breast carcinoma Hs578T cells that express endogenous H-Ras. These results suggest a positive signal amplification loop between flotillin-1 and H-Ras for the invasive signaling program in breast epithelial cells. Importantly, tissue microarrays of 289 patients with invasive breast cancer revealed that flotillin-1 expression positively correlates with lymph node metastases (p=0.027), HER2/neu oncogene expression (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1062. doi:10.1158/1538-7445.AM2011-1062

Metastatic spread is the major cause of death from breast cancer. The objective of our study is to unveil signal transduction pathways specific to breast epithelial cell invasion and migration apart from cell proliferation/transformation. We previously showed that the active H-Ras, but not N-Ras, induces invasive/migratory phenotypes of MCF10A human breast epithelial cells via activation of Rac1/p38 signaling leading to MMP-2 up-regulation, while both H-Ras and N-Ras induce cell proliferation and transformation. In the present study, we hypothesized that the Ras isoform-specific signaling pathway is initiated by differential involvement of lipid raft proteins. To address this, we characterized proteome profiles of lipid raft proteins from three cell lines: normal MCF10A; N-Ras-transformed, non-invasive MCF10A; and H-Ras-transformed, invasive MCF10A cells. Among twenty-four lipid raft proteins that were up-regulated in an H-Ras-specific manner, we tested whether flotillin-1 plays a causative role for H-Ras-mediated MCF10A cell invasion/migration. Here, we show that flotillin-1 interacts with H-Ras and H-Ras signaling increases flotillin-1 expression, suggesting a signaling amplification loop between flotillin-1 and H-Ras. Importantly, siRNA-mediated flotillin-1 knockdown significantly reduced H-Ras-mediated motility/invasion accompanied with down-regulation of Rac1/p38 and MMP-2. We also show that flotillin-1 co-localizes with H-Ras in the plasma membrane, while the interaction between flotillin-1 and N-Ras was negligible. Taken together, this study identified flotillin-1 as an H-Ras-interacting lipid raft protein critical for activation of H-Ras-specific signaling resulting invasive phenotype in breast epithelial cells. Consistently, flotillin-1 mRNA was significantly higher in malignant breast cancer tissues, supporting our hypothesis that flotillin-1 may contribute to breast carcinoma invasion. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5197.

Previously, we reported that DNA copy number of NFIB is amplified in triple negative breast cancer (TNBC; estrogen(−)/progesterone(−)/HER2(−)). The transcriptional activator NFIB plays wide roles in regulation of gene transcription, cell proliferation, viral DNA replication and development. But the functional role of NFIB in breast cancer cell has not been elucidated. In order to understand the role of upregulated NFIB in breast cancers, we examined mRNA and protein level of NFIB in 20 breast cancer tissues. In ER negative breast cancer subtype, expression of NFIB is up-regulated and correlated with Ki67 expression. And intracellular localization of NFIB is restricted in nucleus. In ER negative cell line, knock-down of NFIB leads to reduced cell proliferation by cell cycle arrest. Cell cycle arrest is accompanied by S phase arrest and alteration of S phase regulating protein expression. Take together, transcription activator of NFIB regulates cancer cell proliferation in ER negative breast cancer and it may act as a therapeutic marker. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C26.

Abstract #5006 Although every effort has been made to discover single potent biomarkers in oncology, the promising single biomarker often loses its clinical potency in the course of clinical validations. We aimed to construct and verify a biomarker panel with multiple proteins for breast cancer diagnosis. Using Surface-Enhanced Laser Desorption/ Ionization Time-of-Flight mass spectrometry (SELDI-TOF-MS) and microbead array system, epidermal growth factor (EGF), vascular cell adhesion molecule-1 (VCAM-1), CD40L, vitronectin, plasminogen activation inhibitor-1 (PAI-1), vitamin-D binding protein (VDBP), C-reactive protein (CRP), kininogen, apolipoprotein A1 and proapolipoprotein A1 were identified and validated as useful biomarkers for detection of breast cancer. The multiplexing panel (MP) which was constructed by combining algorithm (random forest, support vector machine) with above biomarkers showed that the diagnostic accuracy approached 91% in 216 test samples. A following double blind test verified that the diagnostic accuracy of the MP was 68% with an additional validation set including sera from 49 patients with breast cancer and 51 healthy women (sensitivity=74%; 95% confidence interval (CI)=58.9–85.0%, specificity=62.7%; 95% CI=48.1–75.9%, positive predictive value=65.5%; 95% CI=55.7-75.3%, negative predictive value=71.7%; 95% CI=61.7-80.35%). We suggest that these results support the potential use of the MP as an early detector of breast cancer. In order to validate the role and potency of the MP in routine clinical practice, a large scale clinical validation in a cohort consisting of 500 patients with breast cancer and the same number of healthy women are underway and the results will be released in the near future. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5006.

Abstract #1086 Purpose: We sought to determine the significance of Ki-67, one of the tumor cell proliferation indexes, as a useful prognostic factor in early breast cancer. Patients and Methods: 1,080 consecutive patients with stage I or II breast cancer operated between 1998 and 2003 were enrolled. Patients were categorized based on the 2007 St. Gallen consensus and Adjuvant! Online. The expression of Ki-67 in the tumor was assayed using immunohistochemistry (cut-off value: 10%). Results: Univariate analysis revealed that tumor size, lymph node involvement, histologic grade, estrogen receptor, progesterone receptor, bcl-2, and Ki-67 (≥10%) were significant for both overall survival (OS) and distant metastasis-free survival (DFS). Of them, lymph node involvement and high Ki-67 expression were identified as independent prognostic factors for OS at multivariate analysis. The survivals of intermediate- and high-risk groups according to 2007 St Gallen consensus were further separated by Ki-67 expression level (5-yr DFS rate=93.3% vs 86.6% for Ki-67 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1086.