Abstract
Purpose
Caspase-8 is an initiator caspase, which regulates apoptosis and stimulates cell proliferation, malignant transformation and tumour progression. The CASP8 gene often disrupts the apoptotic mechanism and poses a risk of developing various types of cancer. The prognostic role of caspase-8 in breast cancer has been a subject of great interest and has not been validated yet. This pilot study was aimed to evaluate the expression of caspase-8 in breast cancer patients and its correlation with the disease outcome.
Design
In this study, 50 patients of breast cancer were enrolled. The immunohistochemical expression of Caspase-8, Estrogen Receptor (ER) and Progesterone Receptor (PR) and Her2/neu was studied and correlated with other prognostic factors.
Results
In case of weak/negative caspase-8 staining, 60% cases had 2 to 5 cm size followed by 36% which were > 5 cm in size. Out of 28 cases with moderate caspase-8 staining, 78.5% cases had tumour of 2 to5 cm in size and 21.4% had size > 5 cm size and out of 17 cases with strong caspase-8 staining, 58.8% had > 5 cm size, followed by 29.4% which had 2 to 5 cm and 11.7% with < 2 cm size. Both the cases (100%) with tumour size < 2 cm had strong caspase-8 staining (p = 0.05). There was no significant correlation between caspase-8 staining with histological grade, lymph node involvement, ER, PR and Her2/neu (p = 0.50, 0.50, 0.68, 0.55 and 0.26, respectively) staining. Except for lymph node involvement (p = 0.01), there was no significant caspase-8 staining correlation with survival, tumour size and histological tumour grade on follow-up (p = 0.42, 0.87 and 0.36, respectively).
Conclusion
Most of the breast cancers overexpress caspase-8. Survival of patients correlated only with lymph node involvement. It was better when there was weak or negative caspase-8 staining, though not statistically significant. Caspase-8 may have a potential for use in future as one of the prognostic biomarker if the larger study is able to establish the significance in breast cancer.
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References
Nagata S, Tanaka M. Programmed cell death and the immune system. Nat Rev Immunol. 2017;17(5):333–40.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.
Julien O, Wells J. Caspases and their substrates. Cell Death Differ. 2017;24:1380–9.
Siegmund D, Mauri D, Peters N, Juo P, Thome M, Reichwein M, Blenis J, Scheurich P, Tschopp J, Wajant H. Fas-associated death domain protein (FADD) and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a FLICE inhibitory protein (FLIP)-regulated pathway. J Biol Chem. 2001;276(35):32585–90.
Tummers B, Green DR. Caspase-8: regulating life and death. Immunol Rev. 2017;277(1):76–89.
Jager R, Zwacka RM. The enigmatic roles of caspases in tumor development. Cancers. 2010;2(4):1952–79.
Grenet J, Teitz T, Wei T, Valentine V, Kidd VJ. Structure and chromosome localization of the human CASP8 gene. Gene. 1999;226(2):225–32.
McGuffog L, Antoniou AC, Stoppa-Lyonnet D, Sinilnikova OM, Barjhoux L, Frenay M, Michel C, et al. Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2010;19(11):2859–68.
Yang S, Liu J, Thor AD, Yang X. Caspase expression profile and functional activity in a panel of breast cancer cell lines. Oncol Rep. 2007;17(5):1229–35.
De Blasio A, Di Fiore R, Morreale M, Carlisi D, Drago-Ferrante R, Montalbano M, et al. Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. Int J Oncol. 2016;48:2339–48.
Pingoud-Meier C, Lang D, Janss AJ, Rorke LB, Phillips PC, Shalaby T, Grotzer MA. Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma. Clin Cancer Res. 2003;9(17):6401–9.
Skiriute D, Vaitkiene P, Saferis V, Asmoniene V, Skauminas K, Deltuva VP, et al. MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma. BMC Cancer. 2012;12:218.
Bray F, McCarron P, Parkin DM. The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res. 2004;6(6):229–39.
National Centre for Disease informatics and Research. National Cancer Registry Programme: Five years Report of Population Based Cancer Registry, Wardha District: 2010–14, Maharashtra, India. Indian Council of Medical Research; 2016:14.
Vakkala M, Paakko P, Soini Y. Expression of caspases 3, 6 and 8 is increased in parallel with apoptosis and histological aggressiveness of the breast lesion. Br J Cancer. 1999;81(4):592–9.
Ma H, Lu Y, Marchbanks PA, Folger SG, Strom BL, McDonald JA, et al. Quantitative measures of estrogen receptor expression in relation to breast cancer-specific mortality risk among white women and black women. Breast Cancer Res. 2013;15(5):R90.
Bansal C, Sharma A, Pujani M, Pujani M, Sharma KL, Srivastava AN, Singh US. Correlation of hormone receptor and human epidermal growth factor receptor-2/neu expression in breast cancer with various clinicopathologic factors. Indian J Med Paediatr Oncol. 2017;38(4):483–9.
Pu X, Storr SJ, Zhang Y, Rakha EA, Green AR, Ellis IO, Martin SG. Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival. Apoptosis. 2017;22(3):357–68.
Virkajarvi N, Paakko P, Soini Y. Apoptotic index and apoptosis influencing proteins bcl-2, mcl-1, bax and caspases 3, 6 and 8 in pancreatic carcinoma. Histopathology. 1998;33(5):432–9.
Kang Z, Goldstein SD, Yu Y, Meltzer PS, Loeb DM, Cao L. Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing’s sarcoma. Br J Cancer. 2015;113(6):894–901.
Liu D, Xu W, Ding X, Yang Y, Lu Y, Fei K, Su B. Caspase 8 polymorphisms contribute to the prognosis of advanced lung adenocarcinoma patients after platinum-based chemotherapy. Cancer Biol Ther. 2017;18(12):948–57.
Polanski R, Vincent J, Polanska UM, Petreus T, Tang EK. Caspase-8 activation by TRAIL monotherapy predicts responses to IAPi and TRAIL combination treatment in breast cancer cell lines. Cell Death Dis. 2015;6(10):e1893.
Zoli W, Ulivi P, Tesei A, Fabbri F, Rosetti M, Maltoni R, et al. Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines. Breast Cancer Res. 2005;7:R681.
Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene. 2001;20(41):5865–77.
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Kotalwar, K.S., Deshmukh, A.V. & Gangane, N.M. Role of Caspase-8 as a Prognostic Biomarker in Breast Cancer—A Pilot Study in Central India. Indian J Gynecol Oncolog 19, 74 (2021). https://doi.org/10.1007/s40944-021-00572-2
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DOI: https://doi.org/10.1007/s40944-021-00572-2