Correlation between Ubiquitin E3 Ligases (SIAHs) and Heat Shock Protein 90 in Breast Cancer Patients
Abstract
Background: Breast cancer is a heterogeneous disease and differences in the expression levels of the ER, PR, and HER2 the triplet of established biomarkers used for clinical decision-making have been reported among breast cancer patients. Furthermore, resistance to anti-estrogen and anti-HER2 therapies emerges in a considerable rate of breast cancer patients, and novel drug therapies are required. Several anomalous signaling pathways have been known in breast cancer have been known; heat shock protein 90 (HSP90) is one of the most plenty proteins in breast cells. The family of ubiquitin ligases such as SIAH1 and SIAH2 is known to specifically target misfolded proteins to the proteasome; also, they have been illustrated to play a role in RAS signaling and as an essential downstream signaling component required for EGFR/HER2 in breast cancer.
Methods: The expression of SIAH2, HSP90, and HER2 was assessed by quantitative Real-Time PCR in 85 invasive ductal carcinoma breast tumor samples at Uludag University Hospital in Turkey during the years 2018–2019, and its association with the clinicopathologic variables of patients was evaluated.
Results: HSP90, SIAH1, and SIAH2 were significantly (P=0.0271, P=0.022, and P=0.0311) upregulated tumor tissue of patients with breast cancer. Moreover, this study observed a significant association between the high expression of SIAH2/ HSP90 with ER status, high expression of HSP90 with Recurrence/ Metastasis, and high expression of SIAH2 with Ki-67 proliferation index.
Conclusion: The HSP90 and SIAH2 expressions play a significant role in breast cancer development by combining the experimental and clinical data obtained from the literature.
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19. Finley D, Sadis S, Monia BP et al (1994). Inhibition of proteolysis and cell cycle progression in a multiubiquitination-deficient yeast mutant. Mol Cell Biol, 14:5501-9.
20. Hershko A (1983). Ubiquitin: roles in protein modification and breakdown. Cell, 34:11-2.
21. Hershko A (2005). The ubiquitin system for protein degradation and some of its roles in the control of the cell-division cycle (Nobel lecture). Angew Chem Int Ed Engl, 44:5932-43.
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23. Glickman MH, Ciechanover A (2002). The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev, 82:373-428.
24. Samant RS, Clarke PA, Workman P (2014). E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells. Proc Natl Acad Sci U S A, 111:6834-9.
25. Interiano RB, Yang J, Harris AL, Davidoff AM (2014). Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells. J Surg Res, 190:203-9.
26. Behling KC, Tang A, Freydin B et al (2011). Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma. Breast Cancer Res Treat, 129:717-24.
27. van Reesema LLS, Zheleva V, Winston JS et al (2016). SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer. EBioMedicine, 11:183-198.
28. Xu Z, Sproul A, Wang W et al (2006). Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. J Biol Chem, 281:303-12.
29. House CM, Moller A, Bowtell DD (2009). Siah proteins: novel drug targets in the Ras and hypoxia pathways. Cancer Res, 69:8835-8.
30. Knauer SK, Mahendrarajah N, Roos WP, Kramer OH (2015). The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers. Cytokine Growth Factor Rev, 26:405-13.
31. Neckers L, Ivy SP (2003). Heat shock protein 90. Curr Opin Oncol, 15:419-24.
32. Zhang H, Burrows F (2004). Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med (Berl), 82:488-99.
33. Dimas DT, Perlepe CD, Sergentanis TN et al (2018). The Prognostic Significance of Hsp70/Hsp90 Expression in Breast Cancer: A Systematic Review and Meta-analysis. Anticancer Res, 38:1551-1562.
34. Zagouri F, Nonni A, Sergentanis TN et al (2008). Heat shock protein90 in lobular neoplasia of the breast. BMC Cancer, 8:312.
35. Zagouri F, Sergentanis TN, Nonni A et al (2010). Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions. BMC Cancer, 10:353.
36. Jhaveri K, Wang R, Teplinsky E et al (2017). A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res, 19:89.
37. Siswanto FM, Jawi IM, Kartiko BH (2018). The role of E3 ubiquitin ligase seven in absentia homolog in the innate immune system: An overview. Vet World, 11:1551-1557.
38. Adam MG, Matt S, Christian S et al (2015). SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status. Cell Cycle, 14:3734-47.
39. Nakayama K, Frew IJ, Hagensen M et al (2004). Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell, 117:941-52.
40. Chan P, Moller A, Liu MC et al (2011). The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression. Breast Cancer Res, 13:R19.
41. Fay MJ, Longo KA, Karathanasis GA et al (2003). Analysis of CUL-5 expression in breast epithelial cells, breast cancer cell lines, normal tissues and tumor tissues. Mol Cancer, 2:40.
2. Chatterjee SK, Zetter BR (2005). Cancer biomarkers: knowing the present and predicting the future. Future Oncol, 1:37-50.
3. Duffy MJ, Harbeck N, Nap M et al (2017). Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer, 75:284-298.
4. Cuzick J, Dowsett M, Pineda S et al (2011). Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol, 29:4273-8.
5. Ciocca DR, Fujimura FK, Tandon AK et al (1992). Correlation of HER-2/neu amplification with expression and with other prognostic factors in 1103 breast cancers. J Natl Cancer Inst, 84:1279-82.
6. Duffy MJ, O'Donovan N, McDermott E, Crown J (2016). Validated biomarkers: The key to precision treatment in patients with breast cancer. Breast, 29:192-201.
7. Ross JS, Fletcher JA, Bloom KJ et al (2004). Targeted therapy in breast cancer: the HER-2/neu gene and protein. Mol Cell Proteomics, 3:379-98.
8. Gianni L, Pienkowski T, Im YH et al (2012). Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol, 13:25-32.
9. Wilks ST (2015). Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast, 24:548-55.
10. Arribas J, Baselga J, Pedersen K, Parra-Palau JL (2011). p95HER2 and breast cancer. Cancer Res, 71:1515-9.
11. Berezowska S, Novotny A, Bauer K A et al (2013). Association between HSP90 and Her2 in gastric and gastroesophageal carcinomas. PLoS One, 8:e69098.
12. Cheng Q, Chang JT, Geradts J et al (2012). Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. Breast Cancer Res, 14:R62.
13. Trepel J, Mollapour M, Giaccone G, Neckers L (2010). Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer, 10:537-49.
14. Pick E, Kluger Y, Giltnane JM et al (2007). High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res, 67:2932-7.
15. Zagouri F, Bournakis E, Koutsoukos K, Papadimitriou CA (2012). Heat shock protein 90 (hsp90) expression and breast cancer. Pharmaceuticals (Basel), 5:1008-20.
16. Jarzab M, Kowal M, Bal W et al (2016). Ratio of proliferation markers and HSP90 gene expression as a predictor of pathological complete response in breast cancer neoadjuvant chemotherapy. Folia Histochem Cytobiol, 54:202-209.
17. Zagouri F, Sergentanis TN, Chrysikos D et al (2013). Hsp90 inhibitors in breast cancer: a systematic review. Breast, 22:569-78.
18. Kirkpatrick DS, Hathaway NA, Hanna J et al (2006). Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology. Nat Cell Biol, 8:700-10.
19. Finley D, Sadis S, Monia BP et al (1994). Inhibition of proteolysis and cell cycle progression in a multiubiquitination-deficient yeast mutant. Mol Cell Biol, 14:5501-9.
20. Hershko A (1983). Ubiquitin: roles in protein modification and breakdown. Cell, 34:11-2.
21. Hershko A (2005). The ubiquitin system for protein degradation and some of its roles in the control of the cell-division cycle (Nobel lecture). Angew Chem Int Ed Engl, 44:5932-43.
22. Hochstrasser M (1996). Ubiquitin-dependent protein degradation. Annu Rev Genet, 30:405-39.
23. Glickman MH, Ciechanover A (2002). The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev, 82:373-428.
24. Samant RS, Clarke PA, Workman P (2014). E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells. Proc Natl Acad Sci U S A, 111:6834-9.
25. Interiano RB, Yang J, Harris AL, Davidoff AM (2014). Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells. J Surg Res, 190:203-9.
26. Behling KC, Tang A, Freydin B et al (2011). Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma. Breast Cancer Res Treat, 129:717-24.
27. van Reesema LLS, Zheleva V, Winston JS et al (2016). SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer. EBioMedicine, 11:183-198.
28. Xu Z, Sproul A, Wang W et al (2006). Siah1 interacts with the scaffold protein POSH to promote JNK activation and apoptosis. J Biol Chem, 281:303-12.
29. House CM, Moller A, Bowtell DD (2009). Siah proteins: novel drug targets in the Ras and hypoxia pathways. Cancer Res, 69:8835-8.
30. Knauer SK, Mahendrarajah N, Roos WP, Kramer OH (2015). The inducible E3 ubiquitin ligases SIAH1 and SIAH2 perform critical roles in breast and prostate cancers. Cytokine Growth Factor Rev, 26:405-13.
31. Neckers L, Ivy SP (2003). Heat shock protein 90. Curr Opin Oncol, 15:419-24.
32. Zhang H, Burrows F (2004). Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med (Berl), 82:488-99.
33. Dimas DT, Perlepe CD, Sergentanis TN et al (2018). The Prognostic Significance of Hsp70/Hsp90 Expression in Breast Cancer: A Systematic Review and Meta-analysis. Anticancer Res, 38:1551-1562.
34. Zagouri F, Nonni A, Sergentanis TN et al (2008). Heat shock protein90 in lobular neoplasia of the breast. BMC Cancer, 8:312.
35. Zagouri F, Sergentanis TN, Nonni A et al (2010). Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions. BMC Cancer, 10:353.
36. Jhaveri K, Wang R, Teplinsky E et al (2017). A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer. Breast Cancer Res, 19:89.
37. Siswanto FM, Jawi IM, Kartiko BH (2018). The role of E3 ubiquitin ligase seven in absentia homolog in the innate immune system: An overview. Vet World, 11:1551-1557.
38. Adam MG, Matt S, Christian S et al (2015). SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status. Cell Cycle, 14:3734-47.
39. Nakayama K, Frew IJ, Hagensen M et al (2004). Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell, 117:941-52.
40. Chan P, Moller A, Liu MC et al (2011). The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression. Breast Cancer Res, 13:R19.
41. Fay MJ, Longo KA, Karathanasis GA et al (2003). Analysis of CUL-5 expression in breast epithelial cells, breast cancer cell lines, normal tissues and tumor tissues. Mol Cancer, 2:40.
| Files | ||
| Issue | Vol 51 No 8 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v51i8.10270 | |
| Keywords | ||
| Breast cancer Invasive ductal carcinoma Ubiquitin-protein ligases | ||
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How to Cite
1.
Sabour Takanlou L, Cecener G, Sabour Takanlou M, Ozturk Nazlioglu H, Tezcan Unlu H, Isik O, Egeli U, Tunca B, Cubukcu E, Tolunay S, Sehsuvar Gokgoz M. Correlation between Ubiquitin E3 Ligases (SIAHs) and Heat Shock Protein 90 in Breast Cancer Patients. Iran J Public Health. 2022;51(8):1836-1846.
