title: SMAD4 is a potential prognostic marker in human breast carcinomas.
abstract: SMAD4 is a downstream mediator of transforming growth factor beta. While its tumor suppressor function has been investigated as a prognostic biomarker in several human malignancies, its role as a prognostic marker in breast carcinoma is still undefined. We investigated SMAD4 expression in breast carcinoma samples of different histologic grades to evaluate the association between SMAD4 and outcome in breast cancer. We also investigated the role of SMAD4 expression status in MDA-MB-468 breast cancer cells in responding to TGF-β stimulation. SMAD4 expression was assessed in 53 breast ductal carcinoma samples and in the surrounding normal tissue from 50 of the samples using immunohistochemistry, Western blot, and real-time PCR. TGF-β-SMAD and non-SMAD signaling was assessed by Western blot in MDA-MB-468 cells with and without SMAD4 restoration. SMAD4 expression was reduced in ductal breast carcinoma as compared to surrounding uninvolved ductal breast epithelia (p < 0.05). SMAD4 expression levels decreased from Grade 1 to Grade 3 ductal breast carcinoma as assessed by immunohistochemistry (p < 0.05). Results were recapitulated by tissue array. In addition, immunohistochemistry results were further confirmed at the protein and mRNA level. We then found that non-SMAD MEK/MAPK signaling was significantly different between SMAD4 expressing MDA-MB-468 cells and SMAD4-null MDA-MB-468 cells. This is the first study indicating that SMAD4 plays a key role in shifting MAPK signaling. Further, we have demonstrated that SMAD4 has a potential role in the development of breast carcinoma and SMAD4 was a potential prognostic marker of breast carcinoma. Our findings further support the role of SMAD4 in breast carcinoma development. In addition, we observed an inverse relationship between SMAD4 levels and breast carcinoma histological grade. Our finding indicated that SMAD4 expression level in breast cancer cells played a role in responding non-SMAD signaling but not the canonic SMAD signaling. Further mechanistic studies are necessary to establish the role of SMAD4 in breast carcinoma prognosis and potential specific targeting.
authors: The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China, liunn1976@163.com.
authors: Nan-nan
authors: NN
authors: Liu
authors: Yue
authors: Y
authors: Xi
authors: Michael U
authors: MU
authors: Callaghan
authors: Andrew
authors: A
authors: Fribley
authors: Lakisha
authors: L
authors: Moore-Smith
authors: Jacquelyn W
authors: JW
authors: Zimmerman
authors: Boris
authors: B
authors: Pasche
authors: Qinghua
authors: Q
authors: Zeng
authors: Yu-lin
authors: YL
authors: Li
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C497796:SMAD4 protein, human; D051901:Smad4 Protein
references: Nat Med. 1996 Jul;2(7):811-4
references: 8673929
references: Int J Biol Sci. 2010 Jan 01;6(1):1-8
references: 20087440
references: J Clin Invest. 2003 Oct;112(7):1116-24
references: 14523048
references: Cancer Epidemiol Biomarkers Prev. 2010 Aug;19(8):1893-907
references: 20647400
references: Gene Expr. 2011;15(3):117-32
references: 22268294
references: Biol Chem. 2005 Mar;386(3):225-36
references: 15843168
references: Cell Res. 2002 Mar;12(1):9-18
references: 11942415
references: Anticancer Res. 2007 Jul-Aug;27(4C):2613-20
references: 17695423
references: Cancer Res. 2006 Aug 15;66(16):8007-16
references: 16912176
references: Arch Gynecol Obstet. 2011 Dec;284(6):1543-9
references: 21448710
references: Breast Cancer Res. 2005;7(6):R1058-79
references: 16457687
references: Oncogene. 1997 Apr 24;14(16):1891-9
references: 9150356
references: Cancer Res. 2006 Feb 15;66(4):2202-9
references: 16489022
references: J Biol Chem. 2003 Jan 31;278(5):3275-85
references: 12421823
references: Oncogene. 2007 Apr 12;26(17):2407-22
references: 17072348
references: J Hepatobiliary Pancreat Surg. 2007;14(3):224-32
references: 17520196
references: Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1681-5
references: 16030101
references: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1427-32
references: 9990040
references: J Clin Invest. 1999 Jan;103(2):197-206
references: 9916131
references: Cancer Res. 2008 Mar 1;68(5):1319-28
references: 18316594
references: Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30
references: 22992590
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: Cancer Res. 2002 Jan 15;62(2):497-505
references: 11809701
references: Nature. 2011 Feb 10;470(7333):269-73
references: 21289624
references: Curr Opin Oncol. 2005 Jan;17(1):49-54
references: 15608513
references: J Pathol. 2011 Jan;223(2):307-17
references: 21125683
references: J Biol Chem. 2005 Jul 22;280(29):27022-8
references: 15886208
references: Cell Res. 2009 Jan;19(1):128-39
references: 19114990
references: J Biol Chem. 2002 Jul 5;277(27):24571-8
references: 11964407
references: Breast Cancer Res Treat. 2011 Aug;128(3):657-66
references: 20821046
references: Cancer Chemother Pharmacol. 2011 Jul;68(1):79-86
references: 20844878
references: Cancer Res. 2008 Mar 15;68(6):1656-66
references: 18339844
references: Mol Cancer. 2009 Nov 27;8:111
references: 19943940
references: BMC Cancer. 2006 Jan 26;6:25
references: 16438724
references: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13909-14
references: 16172383
references: Br J Cancer. 2002 Sep 9;87(6):630-4
references: 12237773
references: Mol Cell Biol. 2008 Nov;28(22):6889-902
references: 18794361
references: EMBO J. 2009 Jan 21;28(2):88-98
references: 19096363
references: Nat Med. 2009 Aug;15(8):960-6
references: 19597504
references: J Clin Oncol. 2008 Sep 10;26(26):4282-8
references: 18779615
references: Mod Pathol. 2001 Jul;14(7):672-6
references: 11454999