Runx2 Expression as a Potential Prognostic Marker in Invasive Ductal Breast Carcinoma
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The Runx family of transcription factors has been implicated in cancer progression, both positively and negatively. Recent studies assigned a role for Runx2 in promoting breast cancer metastasis. However, the role of Runx2 during the early stage of breast carcinoma and its association with clinical outcomes remain unknown. Assessing the clinicopathological significance of Runx2 expression in a cohort of breast invasive ductal carcinomas (IDC). The correlation of nuclear Runx2 LI with clinicopathological parameters was assessed in 84 IDCs. To study the association of Runx2 with patient outcomes, in addition to treating it as a continuous variable, Runx2 was categorized by its median value (65) and by an additional two cut-off points determined by ROC curve analyses, at 45 for disease free survival (DFS) and 40 for overall survival (OS). Multivariate Cox regression models were also constructed. We used the best subset regression to identify models that predict DFS and OS with as few predictors as possible, and validation was performed. Based on the “Predicted R2”, the three best models were identified. Using Cox-regression, the interaction between Runx2 and other clinicopathological terms was tested. Runx2 LI was significantly associated only with positive Her-2 status, and did not correlate significantly with other clinicopathological parameters. Although Runx2 LI, in the continuous form and when categorized by the median, did not correlate significantly with DFS and OS; after it was categorized using the optimal cut-off points determined using ROC curve analysis, the patients with Runx2 LI >45 % showed a significantly higher event rate and shorter DFS (P = 0.047), whereas patients with Runx2 LI >40 % showed a significantly shorter OS (P = 0.050). Moreover, Runx2 LI contributed significantly in the models built to predict DFS and OS. For DFS, no interaction terms contributed significantly to the models. However, among stage IV cases, the interaction term between centred Runx2 and ER significantly contributed to the prediction of OS. Runx2 was a significant predictor of OS in this model. Runx2 has a role in biological behaviour and affects the outcome of IDC; therefore, its inhibition may be a new therapeutic strategy. The predictability of Runx2 for OS in stage IV tumours differs with different ER states. The pattern of this difference was not determined because the sample size was not sufficient to allow pattern testing.
KeywordsRunx2 Breast carcinoma Prognostic factor Clinical outcome Survival
The authors appreciate all technicians at Department of Pathology, Alexandria University, Egypt.
Compliance with Ethical Standards
Conflict of Interest
The authors have no conflicts of interest.
- 2.Gnant M, Dubsky P, Fitzal F, Blaha P, Schoppmann S, Steger G, Marth C, Samonigg H, Hüttner K, Fohler H, Ruecklinger E, Jakesz R, Greil R, Austrian Breast and Colorectal Cancer Study Group (2009) Maintaining bone density in patients undergoing treatment for breast cancer: is there an adjuvant Benefit? Clin Breast Cancer 9(Suppl 1):S18–S27CrossRefPubMedGoogle Scholar
- 11.Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA (24) 289:3243–3253.Google Scholar
- 14.Chimge NO, Baniwal SK, Luo J, Coetzee S, Omar Khalid O, Berman B, Tripathy D, Ellis M, Frenkel B (2012) Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally-regulated gene signature related to clinical letrozole responsiveness. Clin Cancer Res 18(3):901–911CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Levanon D, Glusman G, Bettoun D, Ben-Asher E, Negreanu V, Bernstein Y, Harris-Cerruti C, Brenner O, Eilam R, Lotem J, Fainaru O, Goldenberg D, Pozner A, Woolf E, Xiao C, Yarmus M, Groner Y (2003) Phylogenesis and regulated expression of the RUNT domain transcription factors RUNX1 and RUNX3. Blood Cells Mol Dis 30(2):161–163CrossRefPubMedGoogle Scholar
- 19.Zaidi SK, Pande S, Pratap J, Gaur T, Grigoriu S, Ali SA, Stein JL, Lian JB, van Wijnen AJ, Stein GS (2007) Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential. Proc Natl Acad Sci U S A 104:19861–19866CrossRefPubMedPubMedCentralGoogle Scholar
- 20.. Blyth K, Vaillant F, Jenkins A, McDonald L, Pringle MA, Huser C, Stein T, Neil J, Cameron ER (2010) Runx2 in normal tissues and cancer cells: a developing story. Blood Cells, Molecules & Diseases. 45 (2):117–123.Google Scholar
- 22.Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2005) Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Proc Natl Acad Sci U S A 102:1454–1459CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Pratap J, Imbalzano KM, Underwood JM, Cohet N, Gokul K, Akech J, van Wijnen AJ, Stein JL, Imbalzano AN, Nickerson JA, Lian JB, Stein GS (2009) Ectopic runx2 expression in mammary epithelial cells disrupts formation of normal acini structure: implications for breast cancer progression. Cancer Res 69:6807–6814CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Pratap J, Wixted JJ, Gaur T, Zaidi SK, Dobson J, Gokul KD, Hussain S, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2008) Runx2 transcriptional activation of Indian hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res 68:7795–7802CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC, Pratap J, Keller E, Stein GS, Lian JB (2010) Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 29:811–821CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Zelzer E, Glotzer DJ, Hartmann C, Thomas D, Fukai N, Soker S, Olsen BR (2001) Tissue specific regulation of VEGF expression during bone development requires Cbfa1 ⁄ Runx2. Mech Dev 106 (1–2): 97–106.Google Scholar
- 30.Barnes GL, Javed A, Waller SM, Kamal MH, Hebert KE, Hassan MQ, Bellahcene A, Van Wijnen AJ, Young MF, Lian JB, Stein GS, Gerstenfeld LC (2003) Osteoblast-related transcription factors Runx2 (Cbfa1 ⁄ AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res 63(10):2631–2637PubMedGoogle Scholar
- 31.Das K, Leong DT, Gupta A, Shen L, Putti T, Stein GS, van Wijnen AJ, Salto-Tellez M (2009) Positive association between nuclear Runx2 and oestrogen-progesterone receptor gene expression characterises a biological subtype of breast cancer. Eur J Cancer 45(13):2239–2248CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Fitzgibbons PL1, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O'Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ (2000) Prognostic factors in breast cancer. College of American pathologists consensus statement 1999. Arch Pathol Lab Med 124 (7):966–978.Google Scholar
- 35.Ellis IO, Bartlett J, Dowsett M, Humphreys S, Jasani B, Miller K, Pinder SE, Rhodes A, Walker R (2004) Best practice no. 176: updated recommendation for HER-2 testing in the UK. J Clin Pathol 57(3):322–327.Google Scholar