Tissue Plasminogen Activator Levels and Risk of Breast Cancer in a Case–Cohort Study on Italian Women: Results from the Moli-sani StudyFunding The analyses conducted in this study were partially supported by the HYPERCAN Study (AIRC “5xMILLE” no. 12237) and by POR FESR 2014-2020: DD no. 459 del 27/11/2018 (SATIN: Sviluppo di Approcci Terapeutici INnovativi per patologie neoplastiche resistenti ai trattamenti). The enrolment phase of the Moli-sani Study was supported by unrestricted research grants from the Pfizer Foundation (Rome, Italy), the Italian Ministry of University and Research (MIUR, Rome, Italy)—Programma Triennale di Ricerca, Decreto no.1588, and Instrumentation Laboratory, Milan, Italy.
The follow-up phase of the Moli-sani Study (assessment of incident cases) was partially supported by AIRC “5xMILLE” (HYPERCAN Study, n. 12237) and the Italian Ministry of Health (PI GdG, CoPI SC; grant no. RF-2018-12367074).
No funder had a role in study design, collection, analysis, interpretation of data, writing of the manuscript, and decision to submit this article for publication.
Background Elevated levels of key enzymes of the fibrinolytic system, such as tissue plasminogen activator (tPA), are reported as predictors of poor outcome in cancer patients. Limited information is available about their potential predictive value for breast cancer (BC) risk in the general population.
Aim We examined the association of tPA levels with BC risk in a case–cohort study including women from the prospective Moli-sani cohort.
Methods A sample of 710 women (mean age: 54.6 ± 12.1 years) was selected as a subcohort and compared with 84 BC cases, in a median follow-up of 4.2 years. Incident cases of BC were validated through medical records. tPA plasma levels were measured using an enzyme-linked immunosorbent assay kit. Hazard ratio (HR) and 95% confidence interval (CI), adjusted for relevant covariates, were estimated by a Cox regression model using the Prentice method.
Results Compared with the lowest quartile (<4.9 ng/mL), women in the highest quartile of tPA (>11.2 ng/mL) had increased risk of BC (HRIVvsI: 2.20, 95% CI: 1.13–4.28) after adjusted for age, smoking, education, menopause, and residence. Further adjustment for biochemical markers did not modify this association. The risk of BC increased by 34% for each increase in 1 standard deviation of log-transformed tPA levels (p = 0.046). Elevated levels of tPA were associated mainly with estrogen-receptor-positive BC (2.08, 95% CI: 1.18–3.66).
Conclusion Higher levels of tPA, reported to predict cardiovascular risk, are a potential biomarker for BC risk, supporting the hypothesis of a “common soil” linking the pathogenic mechanisms of hormone-dependent tumors and cardiovascular disease.
A.F, L.I., M.B.D, and M.M. contributed to the concept and design of the work and interpretation of data; S.G. and L.R. performed the tPA measurements; S.C., A.D.C. S.G., L.R., M.M., T.P., and M.P. managed data collection; S.C. analyzed the data and reviewed the manuscript; R.P. wrote the manuscript; C.C., M.B.D., A.F., G.d.G., and L.I. originally inspired the research and critically reviewed the manuscript.
* [Supplementary Appendix A] lists all the Moli-sani Investigators.
Received: 08 May 2020
Accepted: 02 September 2020
18 October 2020 (online)
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69 (01) 7-34
- 2 Iacoviello L, Bonaccio M, de Gaetano G, Donati MB. Epidemiology of breast cancer, a paradigm of the “common soil” hypothesis. Semin Cancer Biol 2020; DOI: 10.1016/j.semcancer.2020.02.010.
- 3 Donati MB. The “common soil hypothesis”: evidence from population studies?. Thromb Res 2010; 125 (Suppl. 02) S92-S95
- 4 Danø K, Behrendt N, Høyer-Hansen G. et al. Plasminogen activation and cancer. Thromb Haemost 2005; 93 (04) 676-681
- 5 Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993; 73 (01) 161-195
- 6 Corte MD, Vérez P, Rodríguez JC. et al. Tissue-type plasminogen activator (tPA) in breast cancer: relationship with clinicopathological parameters and prognostic significance. Breast Cancer Res Treat 2005; 90 (01) 33-40
- 7 Layer GT, Burnand KG, Gaffney PJ. et al. Tissue plasminogen activators in breast cancer. Thromb Res 1987; 45 (05) 601-607
- 8 Nielsen VG, Matika RW, Ley ML. et al. Tissue-type plasminogen activator-induced fibrinolysis is enhanced in patients with breast, lung, pancreas and colon cancer. Blood Coagul Fibrinolysis 2014; 25 (03) 248-253
- 9 Di Castelnuovo A, Costanzo S, Persichillo M. et al. MOLI-SANI Project Investigators. Distribution of short and lifetime risks for cardiovascular disease in Italians. Eur J Prev Cardiol 2012; 19 (04) 723-730
- 10 Le Polain de Waroux O, Maguire H, Moren A. The case-cohort design in outbreak investigations. Euro Surveill 2012; 17 (25) 17
- 11 Goldhirsch A, Winer EP, Coates AS. et al. Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24 (09) 2206-2223
- 12 Santimone I, Di Castelnuovo A, De Curtis A. et al. MOLI-SANI Project Investigators. White blood cell count, sex and age are major determinants of heterogeneity of platelet indices in an adult general population: results from the MOLI-SANI project. Haematologica 2011; 96 (08) 1180-1188
- 13 Zeller T, Hughes M, Tuovinen T. et al. BiomarCaRE: rationale and design of the European BiomarCaRE project including 300,000 participants from 13 European countries. Eur J Epidemiol 2014; 29 (10) 777-790
- 14 Nuorti JP, Butler JC, Farley MM. et al. Active Bacterial Core Surveillance Team. Cigarette smoking and invasive pneumococcal disease. N Engl J Med 2000; 342 (10) 681-689
- 15 Costanzo S, Mukamal KJ, Di Castelnuovo A. et al. Moli-sani Study Investigators. Alcohol consumption and hospitalization burden in an adult Italian population: prospective results from the Moli-sani study. Addiction 2019; 114 (04) 636-650
- 16 Prentice RL. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 1986; 73: 1-11
- 17 Falanga A, Santoro A, Labianca R. et al. HYPERCAN Study Group. Hypercoagulation screening as an innovative tool for risk assessment, early diagnosis and prognosis in cancer: the HYPERCAN study. Thromb Res 2016; 140 (140) (Suppl. 01) S55-S59
- 18 Falanga A, Donati MB. Pathogenesis of thrombosis in patients with malignancy. Int J Hematol 2001; 73 (02) 137-144
- 19 Donati MB, Lorenzet R. Thrombosis and cancer: 40 years of research. Thromb Res 2012; 129 (03) 348-352
- 20 Lal I, Dittus K, Holmes CE. Platelets, coagulation and fibrinolysis in breast cancer progression. Breast Cancer Res 2013; 15 (04) 207
- 21 Rhone P, Ruszkowska-Ciastek B, Bielawski K. et al. Comprehensive analysis of haemostatic profile depending on clinicopathological determinants in breast cancer patients. Biosci Rep 2018; 38 (02) 38
- 22 Niessner A, Graf S, Nikfardjam M. et al. Circulating t-PA antigen predicts major adverse coronary events in patients with stable coronary artery disease--a 13-year follow-up. Thromb Haemost 2003; 90 (02) 344-350
- 23 Shalia KK, Shah VK, Mashru MR. et al. Circulating thrombotic and haemostatic components in patients with coronary artery disease. Indian J Clin Biochem 2010; 25 (01) 20-28
- 24 Jansson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up. Circulation 1993; 88 (5, Pt 1): 2030-2034
- 25 Geppert A, Graf S, Beckmann R. et al. Concentration of endogenous tPA antigen in coronary artery disease: relation to thrombotic events, aspirin treatment, hyperlipidemia, and multivessel disease. Arterioscler Thromb Vasc Biol 1998; 18 (10) 1634-1642
- 26 Deepa R, Velmurugan K, Saravanan G, Dwarakanath V, Agarwal S, Mohan V. Relationship of tissue plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen with coronary artery disease in South Indian male subjects. J Assoc Physicians India 2002; 50: 901-906
- 27 Gram J, Bladbjerg EM, Møller L, Sjøl A, Jespersen J. Tissue-type plasminogen activator and C-reactive protein in acute coronary heart disease. A nested case-control study. J Intern Med 2000; 247 (02) 205-212
- 28 Iacoviello L, Agnoli C, De Curtis A. et al. Type 1 plasminogen activator inhibitor as a common risk factor for cancer and ischaemic vascular disease: the EPICOR study. BMJ Open 2013; 3 (11) e003725
- 29 Hernestål-Boman J, Jansson JH, Nilsson TK, Eliasson M, Johansson L. Long-term stability of fibrinolytic factors stored at -80 degrees C. Thromb Res 2010; 125 (05) 451-456