Glypican-3 Differentiates Intraductal Carcinoma and Paget's Disease from Other Types of Breast Cancer

Fatemah Ofo Alshammari 1, Anas O Satari 2, Ahmed S Aljabali 3, Yanal S Al-Mahdy 2, Yasmeen J Alabdallat 4, Yahya M Al-Sarayra 5, Mohammad A Alkhojah 5, Abdel Rahman M Alwardat 6, Mansour Haddad 7, Sameeh A Al-Sarayreh 8, Yousef M Al-Saraireh 9

Affiliations

30 December 2022

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doi: 10.3390/medicina59010086

Abstract

Background and Objectives: breast cancer remains the most common health burden affecting females worldwide. Despite developments in breast cancer diagnostic approaches and treatment strategies, the clinical management of metastatic breast cancer remains challenging. Thus, there is a need to identify new biomarkers and novel drug targets for breast cancer diagnosis and therapy. Recently, aberrant glypican-3 (GPC3) expression in cancers has gained considerable interest in cancer research. The studies, however, have yielded contradictory results about GPC3 expression in breast cancer. Therefore, the current study aims to analyse GPC3 expression across a large panel of different breast cancer subtypes. Materials and Methods: GPC3 expression was immunohistochemically evaluated in 230 breast cancer patients along with eight normal tissues and its associations to clinical and demographic characteristics, as well as immunohistochemical biomarkers for breast cancer. Moreover, a public database consisting of breast cancer patients' survival data and GPC3 gene expression information was used to assess the prognostic value of GPC3 in the survival of breast cancer patients. Results: GPC3 expression was only characterised in 7.5% of different histological breast cancer subtypes. None of the normal breast tissues displayed GPC3 expression. Interestingly, all cases of Paget's disease, as well as 42.9% of intraductal and 16.7% of mucinous carcinomas were found to have GPC3 expression, where it was able to significantly discriminate Paget's disease and intraductal carcinoma from other breast cancer subtypes. Importantly, GPC3 expression was found more often in tumours that tested positive for the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), indicating more favourable histological subtypes of breast cancer. Consequently, longer relapse-free survival (RFS) was significantly correlated with higher GPC3 mRNA expression. Conclusions: Our study proposes that GPC3 is a promising breast cancer subtype-specific biomarker. Moreover, GPC3 may have the potential to be a molecular target for the development of new therapeutics for specific subtypes of breast cancer.

Keywords: biomarker; breast cancer; glypican-3; immunohistochemistry; prognosis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1 GPC3 expression in different histological subtypes of breast cancer. Classification was performed according to histopathological subtype. (A): normal breast tissue, (B): invasive ductal carcinoma, (C): invasive lobular carcinoma, (D): intraductal carcinoma, (E): mucinous adenocarcinoma, (F): Paget’s disease. Magnification ×400.

Figure 1 GPC3 expression in different histological subtypes of breast cancer. Classification was performed according to histopathological subtype. (A): normal breast tissue, (B): invasive ductal carcinoma, (C): invasive lobular carcinoma, (D): intraductal carcinoma, (E): mucinous adenocarcinoma, (F): Paget’s disease. Magnification ×400.

Figure 2 GPC3 expression in various types of experimental controls. (A) No GPC3 immunostaining was found in intraductal carcinoma tissue treated with normal goat serum instead of GPC3 primary antibody (negative control); (B) GPC3 expression was exhibited in intraductal carcinoma tissue incubated with GPC3 primary antibody; (C) no GPC3 expression was found in intraductal carcinoma tissue incubated with peptide-blocked primary antibody; (D) high GPC3 expression was displayed in hepatocellular carcinoma tissue treated with GPC3 primary antibody (positive control); and (E) weak GPC3 expression was determined in hepatocellular carcinoma tissue incubated with peptide-blocked primary antibody. Magnification (×400).

Figure 2 GPC3 expression in various types of experimental controls. (A) No GPC3 immunostaining was found in intraductal carcinoma tissue treated with normal goat serum instead of GPC3 primary antibody (negative control); (B) GPC3 expression was exhibited in intraductal carcinoma tissue incubated with GPC3 primary antibody; (C) no GPC3 expression was found in intraductal carcinoma tissue incubated with peptide-blocked primary antibody; (D) high GPC3 expression was displayed in hepatocellular carcinoma tissue treated with GPC3 primary antibody (positive control); and (E) weak GPC3 expression was determined in hepatocellular carcinoma tissue incubated with peptide-blocked primary antibody. Magnification (×400).

Figure 3 GPC3 mRNA expression in breast cancer versus normal healthy breast. * indicates a p-value of ≤0.05.

Figure 3 GPC3 mRNA expression in breast cancer versus normal healthy breast. * indicates a p-value of ≤0.05.

Figure 4 Kaplan–Meier survival curve of breast cancer patients based on GPC3 mRNA expression. (A) Overall survival (OS), and (B) relapse-free survival (RFS).

Figure 4 Kaplan–Meier survival curve of breast cancer patients based on GPC3 mRNA expression. (A) Overall survival (OS), and (B) relapse-free survival (RFS).

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References

  1.  
    1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. - DOI - PubMed
  2.  
    1. Giordano C., La Camera G., Gelsomino L., Barone I., Bonofiglio D., Andò S., Catalano S. The Biology of Exosomes in Breast Cancer Progression: Dissemination, Immune Evasion and Metastatic Colonization. Cancers. 2020;12:2179. doi: 10.3390/cancers12082179. - DOI - PMC - PubMed
  3.  
    1. Afzal S., Hassan M., Ullah S., Abbas H., Tawakkal F., Khan M.A. Breast Cancer; Discovery of Novel Diagnostic Biomarkers, Drug Resistance, and Therapeutic Implications. Front. Mol. Biosci. 2022;9:1129. doi: 10.3389/fmolb.2022.783450. - DOI - PMC - PubMed
  4.  
    1. Lü L., Sun J., Shi P., Kong W., Xu K., He B., Zhang S., Wang J. Identification of circular RNAs as a promising new class of diagnostic biomarkers for human breast cancer. Oncotarget. 2017;8:44096–44107. doi: 10.18632/oncotarget.17307. - DOI - PMC - PubMed
  5.  
    1. Zhou L., Rueda M., Alkhateeb A. Classification of Breast Cancer Nottingham Prognostic Index Using High-Dimensional Embedding and Residual Neural Network. Cancers. 2022;14:934. doi: 10.3390/cancers14040934. - DOI - PMC - PubMed
  6.  
    1. Tabl A.A., Alkhateeb A., ElMaraghy W., Rueda L., Ngom A. A Machine Learning Approach for Identifying Gene Biomarkers Guiding the Treatment of Breast Cancer. Front. Genet. 2019;10:256. doi: 10.3389/fgene.2019.00256. - DOI - PMC - PubMed
  7.  
    1. Li N., Gao W., Zhang Y.-F., Ho M. Glypicans as Cancer Therapeutic Targets. Trends Cancer. 2018;4:741–754. doi: 10.1016/j.trecan.2018.09.004. - DOI - PMC - PubMed
  8.  
    1. Alshammari F., Al-Saraireh Y.M., Youssef A.M.M., Al-Sarayra Y.M., Alrawashdeh H.M. Glypican-1 Overexpression in Different Types of Breast Cancers. OncoTargets Ther. 2021;14:4309–4318. doi: 10.2147/OTT.S315200. - DOI - PMC - PubMed
  9.  
    1. Al-Saraireh Y.M., Alshammari F.O., Youssef A.M., Al-Sarayreh S., Al-Sarayra Y.M., Aborajooh E., Al-Shuneigat J., Alrawashdeh H.M. Screening of Glypican-6 Expression in Benign, Primary and Metastatic Colon Cancers. Clin. Med. Insights Oncol. 2021;15:11795549211036419. doi: 10.1177/11795549211036419. - DOI - PMC - PubMed
  10.  
    1. Wang S.K., Zynger D.L., Hes O., Yang X.J. Discovery and diagnostic value of a novel oncofetal protein: Glypican 3. Adv. Anat. Pathol. 2014;21:450–460. doi: 10.1097/PAP.0000000000000043. - DOI - PubMed
  11.  
    1. Al-Saraireh Y., Alrawashdeh F., Al-Shuneigat J., Alsbou M., Alnawaiseh N., Al-Shagahin H. Screening of Glypican-3 Expression in Human Normal versus Benign and Malignant Tissues: A Comparative Study Glypican-3 expression in cancers. Biosci. Biotechnol. Res. Asia. 2016;13:687–692. doi: 10.13005/bbra/2085. - DOI
  12.  
    1. Al-Saraireh Y.M., Haddadin W.J., Alboaisa N.S., Youssef A.M., Alsbou M.S., Al-Shuneigat J.M., Makeen H.A., Al-Shagahin H.M. Glypican-3 expression in primary and metastatic neuroblastoma. Jordan J. Biol. Sci. 2016;9:4.
  13.  
    1. Castillo L.F., Lago Huvelle M.A., Fujita A., Maia Lobba A.R., Tascón R.S., Romera Garcia T., Armanasco E., Bagnoli F., Oliveira V.M.d., Longo Galvão M.A. Expression of Glypican-3 (GPC3) in malignant and non-malignant human breast tissues. Open Cancer J. 2015;8:12–23. doi: 10.2174/1874079001508010012. - DOI
  14.  
    1. Xiang Y.-Y., Ladeda V., Filmus J. Glypican-3 expression is silenced in human breast cancer. Oncogene. 2001;20:7408–7412. doi: 10.1038/sj.onc.1204925. - DOI - PubMed
  15.  
    1. Baumhoer D., Tornillo L., Stadlmann S., Roncalli M., Diamantis E.K., Terracciano L.M. Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues: A tissue microarray analysis of 4,387 tissue samples. Am. J. Clin. Pathol. 2008;129:899–906. doi: 10.1309/HCQWPWD50XHD2DW6. - DOI - PubMed
  16.  
    1. Moek K.L., Fehrmann R.S.N., van der Vegt B., de Vries E.G.E., de Groot D.J.A. Glypican 3 Overexpression across a Broad Spectrum of Tumor Types Discovered with Functional Genomic mRNA Profiling of a Large Cancer Database. Am. J. Pathol. 2018;188:1973–1981. doi: 10.1016/j.ajpath.2018.05.014. - DOI - PubMed
  17.  
    1. Allred D.C. Problems and solutions in the evaluation of hormone receptors in breast cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008;26:2433–2435. doi: 10.1200/JCO.2007.15.7800. - DOI - PubMed
  18.  
    1. Tang Z., Li C., Kang B., Gao G., Li C., Zhang Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102. doi: 10.1093/nar/gkx247. - DOI - PMC - PubMed
  19.  
    1. Scully O.J., Bay B.-H., Yip G., Yu Y. Breast Cancer Metastasis. Cancer Genom.-Proteom. 2012;9:311–320. - PubMed
  20.  
    1. Al-Saraireh Y.M., Alboaisa N.S., Alrawashdeh H.M., Hamdan O., Al-Sarayreh S., Al-Shuneigat J.M., Nofal M.N. Screening of cytochrome 4Z1 expression in human non-neoplastic, pre-neoplastic and neoplastic tissues. Ecancermedicalscience. 2020;14:1114. doi: 10.3332/ecancer.2020.1114. - DOI - PMC - PubMed
  21.  
    1. Al-Saraireh Y.M., Alshammari F., Youssef A.M.M., Al-Sarayreh S., Almuhaisen G.H., Alnawaiseh N., Al Shuneigat J.M., Alrawashdeh H.M. Profiling of CYP4Z1 and CYP1B1 expression in bladder cancers. Sci. Rep. 2021;11:5581. doi: 10.1038/s41598-021-85188-4. - DOI - PMC - PubMed
  22.  
    1. Al-Saraireh Y.M., Alshammari F., Youssef A.M.M., Al-Sarayra Y.M., Al-Saraireh R.A., Al-Muhaisen G.H., Al-Mahdy Y.S., Al-Kharabsheh A.M., Abufraijeh S.M., Alrawashdeh H.M. Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer. Curr. Oncol. 2021;28:3573–3584. doi: 10.3390/curroncol28050306. - DOI - PMC - PubMed
  23.  
    1. Alshammari F.O.F.O., Al-Saraireh Y.M., Youssef A.M.M., Al-Sarayra Y.M., Alrawashdeh H.M. Cytochrome P450 1B1 Overexpression in Cervical Cancers: Cross-sectional Study. Interact J. Med. Res. 2021;10:e31150. doi: 10.2196/31150. - DOI - PMC - PubMed
  24.  
    1. Al-Saraireh Y.M., Alshammari F., Youssef A.M.M., Al-Tarawneh F., Al-Sarayreh S., Almuhaisen G.H., Satari A.O., Al-Shuneigat J., Alrawashdeh H.M. Cytochrome 4Z1 Expression is Associated with Unfavorable Survival in Triple-Negative Breast Cancers. Breast Cancer. 2021;13:565–574. doi: 10.2147/BCTT.S329770. - DOI - PMC - PubMed
  25.  
    1. Al-Saraireh Y.M., Alshammari F., Youssef A.M.M., Al-Sarayreh S., Almuhaisen G.H., Alnawaiseh N., Al-Shuneigat J.M., Alrawashdeh H.M. Cytochrome 4Z1 Expression is Associated with Poor Prognosis in Colon Cancer Patients. OncoTargets Ther. 2021;14:5249–5260. doi: 10.2147/OTT.S332037. - DOI - PMC - PubMed
  26.  
    1. Al-Saraireh Y.M., Alshammari F., Satari A.O., Al-Mahdy Y.S., Almuhaisen G.H., Abu-Azzam O.H., Uwais A.N., Abufraijeh S.M., Al-Kharabsheh A.M., Al-Dalain S.M., et al. Cytochrome 4Z1 Expression Connotes Unfavorable Prognosis in Ovarian Cancers. Medicina. 2022;58:1263. doi: 10.3390/medicina58091263. - DOI - PMC - PubMed
  27.  
    1. Al-Saraireh Y., Haddadin W., Alboaisa N., Alarjat J., Al-Shuneigat J., Alnawaiseh N. Expression of Chemokine Receptor CXCR4 in Primary and Metastatic Neuroblastoma Expression of CXCR4 in Neuroblastoma. Biomed. Pharmacol. J. 2016;9:425–431. doi: 10.13005/bpj/955. - DOI
  28.  
    1. Yan P.S., Chen C.M., Shi H., Rahmatpanah F., Wei S.H., Caldwell C.W., Huang T.H. Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays. Cancer Res. 2001;61:8375–8380. - PubMed
  29.  
    1. Castillo L.F., Tascón R., Lago Huvelle M.A., Novack G., Llorens M.C., Dos Santos A.F., Shortrede J., Cabanillas A.M., Bal de Kier Joffé E., Labriola L., et al. Glypican-3 induces a mesenchymal to epithelial transition in human breast cancer cells. Oncotarget. 2016;7:60133–60154. doi: 10.18632/oncotarget.11107. - DOI - PMC - PubMed
  30.  
    1. Fernández-Vega I., García O., Crespo A., Castañón S., Menéndez P., Astudillo A., Quirós L.M. Specific genes involved in synthesis and editing of heparan sulfate proteoglycans show altered expression patterns in breast cancer. BMC Cancer. 2013;13:24. doi: 10.1186/1471-2407-13-24. - DOI - PMC - PubMed
  31.  
    1. Grillo P.K., Győrffy B., Götte M. Prognostic impact of the glypican family of heparan sulfate proteoglycans on the survival of breast cancer patients. J. Cancer Res. Clin. Oncol. 2021;147:1937–1955. doi: 10.1007/s00432-021-03597-4. - DOI - PMC - PubMed
  32.  
    1. Peters M.G., Farías E., Colombo L., Filmus J., Puricelli L., Bal de Kier Joffé E. Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. Breast Cancer Res. Treat. 2003;80:221–232. doi: 10.1023/A:1024549729256. - DOI - PubMed
  33.  
    1. Kanehisa M., Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30. doi: 10.1093/nar/28.1.27. - DOI - PMC - PubMed
  34.  
    1. Liu J.-Q., Liao X.-W., Wang X.-K., Yang C.-K., Zhou X., Liu Z.-Q., Han Q.-F., Fu T.-H., Zhu G.-Z., Han C.-Y., et al. Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms. BMC Gastroenterol. 2020;20:415. doi: 10.1186/s12876-020-01560-0. - DOI - PMC - PubMed
  35.  
    1. Wang J.-Y., Wang X.-K., Zhu G.-Z., Zhou X., Yao J., Ma X.-P., Wang B., Peng T. Distinct diagnostic and prognostic values of Glypicans gene expression in patients with hepatocellular carcinoma. BMC Cancer. 2021;21:462. doi: 10.1186/s12885-021-08104-z. - DOI - PMC - PubMed
  36.  
    1. Gatalica Z., Vranic S., Krušlin B., Poorman K., Stafford P., Kacerovska D., Senarathne W., Florento E., Contreras E., Leary A., et al. Comparison of the biomarkers for targeted therapies in primary extra-mammary and mammary Paget’s disease. Cancer Med. 2020;9:1441–1450. doi: 10.1002/cam4.2820. - DOI - PMC - PubMed
  37.  
    1. Ikeda M., Ohkawa S., Okusaka T., Mitsunaga S., Kobayashi S., Morizane C., Suzuki I., Yamamoto S., Furuse J. Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci. 2014;105:455–462. doi: 10.1111/cas.12368. - DOI - PMC - PubMed
  38.  
    1. Tsuchiya N., Hosono A., Yoshikawa T., Shoda K., Nosaka K., Shimomura M., Hara J., Nitani C., Manabe A., Yoshihara H., et al. Phase I study of glypican-3-derived peptide vaccine therapy for patients with refractory pediatric solid tumors. OncoImmunology. 2018;7:e1377872. doi: 10.1080/2162402X.2017.1377872. - DOI - PMC - PubMed

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