High RNA-binding Motif Protein 3 Expression Is Associated with Improved Clinical Outcomes in Invasive Breast Cancer

다국어 초록 (Multilingual Abstract)

Purpose: Expression of RNA-binding motif protein 3 (RBM3) is induced by hypoxia and hypothermia. Recently, high expression of RBM3 was reported to be associated with a good prognosis in colon cancer, prostate cancer, ovarian cancer, and malignant melanoma. Studies on RBM3 in invasive breast carcinoma (IBC), however, are limited. Methods: RBM3 expression was examined using a tissue microarray from 361 patients with IBC. Immunohistochemistry was performed for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 to compare the expression of these markers. For scoring of RBM3 expression, NF (nuclear staining fraction)×NI (nuclear staining intensity) was used. The RBM3 expression score was considered indicative of either low (≤4) or high (>4) expression. Western blot analysis was performed on breast cancer cell lines to evaluate RBM3 expression. Results: Of the total 361 samples, 240 (66.5%) exhibited high RBM3 expression.
High RBM3 expression was significantly associated with positivity for ER (p<0.001), PR (p<0.001), T stage (p<0.001), histologic grade (p<0.001), and % Ki-67 staining (p=0.004). Multivariate analysis revealed that high RBM3 expression was closely associated with prolonged disease-free survival (DFS) (p<0.001) and overall survival (OS) (p<0.001).
Western blot analysis revealed reduced RBM3 expression in HCC1954 (HER2-enriched) and BT-20 (basal-like) cells with an aggressive phenotype. Conclusion: High nuclear RBM3 expression is strongly associated with a prolonged DFS and OS. Furthermore, RBM3 expression is closely associated with good prognostic markers such as ER and PR in IBC. High nuclear RBM3 expression is, therefore, a critical biomarker of favorable clinical outcomes in IBC.

참고문헌 (Reference)

1 Pilotte J, "Widespread regulation of miRNA biogenesis at the Dicer step by the cold-inducible RNAbinding protein, RBM3" 6 : e28446-, 2011

2 Rakha EA, "Triple-negative/basal-like breast cancer: review" 41 : 40-47, 2009

3 Diaz LK, "Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice" 14 : 419-430, 2007

4 Sureban SM, "Translation regulatory factor RBM3 is a proto-oncogene that prevents mitotic catastrophe" 27 : 4544-4556, 2008

5 Wellmann S, "The RNA-binding protein RBM3 is required for cell proliferation and protects against serum deprivation-induced cell death" 67 : 35-41, 2010

6 Goldhirsch A, "Strategies for subtypes: dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011" 22 : 1736-1747, 2011

7 Wolff AC, "Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update" 31 : 3997-4013, 2013

8 Sutherland LC, "RNA binding motif (RBM) proteins: a novel family of apoptosis modulators?" 94 : 5-24, 2005

9 Ehlen A, "RBM3-regulated genes promote DNA integrity and affect clinical outcome in epithelial ovarian cancer" 4 : 212-221, 2011

10 Derry JM, "RBM3, a novel human gene in Xp11.23 with a putative RNA-binding domain" 4 : 2307-2311, 1995

11 Martinez-Arribas F, "Positive correlation between the expression of X-chromosome RBM genes (RBMX, RBM3, RBM10) and the proapoptotic Bax gene in human breast cancer" 97 : 1275-1282, 2006

12 Wellmann S, "Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism" 117 : 1785-1794, 2004

13 Jogi A, "Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer" 22 : 1564-1574, 2009

14 Eroles P, "Molecular biology in breast cancer: intrinsic subtypes and signaling pathways" 38 : 698-707, 2012

15 Jonsson L, "Low RBM3 protein expression correlates with tumour progression and poor prognosis in malignant melanoma: an analysis of 215 cases from the Malmo Diet and Cancer Study" 9 : 114-, 2011

16 Danno S, "Increased transcript level of RBM3, a member of the glycine-rich RNAbinding protein family, in human cells in response to cold stress" 236 : 804-807, 1997

17 Grupp K, "High RNA-binding motif protein 3 expression is an independent prognostic marker in operated prostate cancer and tightly linked to ERG activation and PTEN deletions" 50 : 852-861, 2014

18 Jonsson L, "High RBM3 expression in prostate cancer independently predicts a reduced risk of biochemical recurrence and disease progression" 6 : 91-, 2011

19 Torre LA, "Global cancer statistics, 2012" 65 : 87-108, 2015

20 Ehlen A, "Expression of the RNA-binding protein RBM3 is associated with a favourable prognosis and cisplatin sensitivity in epithelial ovarian cancer" 8 : 78-, 2010

21 Jang HH, "Expression of RNA-binding motif protein 3 (RBM3) and cold-inducible RNA-binding protein (CIRP) is associated with improved clinical outcome in patients with colon cancer" 37 : 1779-1785, 2017

22 Florianova L, "Evaluation of RNA-binding motif protein 3 expression in urothelial carcinoma of the bladder: an immunohistochemical study" 13 : 317-, 2015

23 Boman K, "Decreased expression of RNA-binding motif protein 3 correlates with tumour progression and poor prognosis in urothelial bladder cancer" 13 : 17-, 2013

24 Prat A, "Deconstructing the molecular portraits of breast cancer" 5 : 5-23, 2011

25 Burd CG, "Conserved structures and diversity of functions of RNA-binding proteins" 265 : 615-621, 1994

26 Al-Astal HI, "Cellular functions of RNAbinding motif protein 3 (RBM3): clues in hypothermia, cancer biology and apoptosis" 23 : 828-835, 2016

27 오창모, "Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2013" 대한암학회 48 (48): 436-450, 2016

28 Hammond ME, "American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version)" 134 : e48-e72, 2010

29 Edge SB, "AJCC cancer staging handbook: from the AJCC cancer staging manual" Springer 2010

30 Uhlen M, "A human protein atlas for normal and cancer tissues based on antibody proteomics" 4 : 1920-1932, 2005