Identification of 3q oncogene SEC62 as a marker for distant metastasis and poor clinical outcome in invasive ductal breast cancer
In previous studies, we have shown that SEC62 has an essential function in cell migration, epithelial-to-mesenchymal transition, and endoplasmic reticulum stress tolerance of cancer cells. SEC62 expression correlated with distant and lymph node metastasis and poor outcome in different cancer entities. In this initial study, we investigated SEC62 expression and its possible role as a prognostic and predictive biomarker in breast cancer (BC).
Formalin-fixed, paraffin-embedded tissue samples of 53 BC patients were analyzed by immunohistochemistry. The immunoreactive score (IRS) according to Remmele and Stegner was evaluated and correlated with clinico-pathological findings and overall survival (OS).
We found increased SEC62 protein levels in tumor tissue compared to tumor-free tissue samples from the same patients. Tumors with high SEC62 expression (IRS > 8), or containing isolated cells with high SEC62 staining intensity, independent of the IRS, had more frequently distant metastases (48.4% vs. 18.2%; p = 0.024 and 47.4 vs. 6.7%; p = 0.005, respectively). Overall survival was significantly worse in BC patients with high SEC62 expression (SEC62 IRS > 8) (54.8% vs. 81.8%; p = 0.011) and in cases with isolated high-intensity SEC62 staining cells independently of SEC62 IRS (55.3% vs 93.3%; p = 0.024).
We are the first to describe the SEC62 expression and its correlation to clinicopathological parameters in mammary carcinoma. Our results suggest that SEC62 expression may serve as a prognostic marker for patients with invasive ductal breast cancer.
KeywordsSEC62 Immunohistochemistry Breast cancer Prognostic factor Biomarker Metastasis
The authors gratefully acknowledge the excellent work, motivation, and enthusiasm of Mrs. Barbara Linxweiler and Mrs. Alice Kunz.
FZT project development, data collection and analysis, manuscript writing. JCR review and editing. ML data analysis, review and editing. MK data collection, review and editing. RMB project development, data collection, review and editing. FB review and editing, visualization. CU data collection, review and editing. EFS review and editing. BS review and editing. IJB review and editing.
The study was funded by the Heinrich Dietz Foundation.
Compliance with ethical standards
Conflict of interest
We declare that we have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients provided written consent for the use of their tissue samples. The study was approved by the Ethics Committee of Saarland (No: 183/17).
- 8.Prat A, Cheang MCU, Martín M, Parker JS, Carrasco E, Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TONCMP (2012) Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. J Clin Oncol 31:203–209CrossRefGoogle Scholar
- 11.Jung V, Kindich R, Kamradt J, Jung M, Müller M, Schulz WA, Engers R, Unteregger G, Stӧckle M, Zimmermann R, Wullich B (2006) Genomic and expression analysis of the 3q25-q26 amplification unit reveals TLOC1/SEC62 as a probable target gene in prostate cancer. Mol Cancer Res 4:169–176CrossRefGoogle Scholar
- 12.Greiner M, Kreutzer B, Jung V, Grobholz R, Hasenfus A, Stöhr RF, Tornillo L, Dudek J, Stöckle M, Unteregger G, Kamradt J, Wullich B, Zimmermann R (2011) Silencing of the SEC62 gene inhibits migratory and invasive potential of various tumor cells. Int J Cancer 128:2284–2295. https://doi.org/10.1002/ijc.25580 CrossRefGoogle Scholar
- 14.Bochen F, Adisurya H, Wemmert S, Lerner C, Greiner M, Zimmermann R, Hasenfus A, Wagner M, Smola S, Pfuhl T, Bozzato A, Kadah BA, Schick B, Linxweiler M (2017) Effect of 3q oncogenes SEC62 and SOX2 on lymphatic metastasis and clinical outcome of head and neck squamous cell carcinomas. Oncotarget 8:4922CrossRefGoogle Scholar
- 16.Hagerstrand D, Tong A, Schumacher SE, Ilic N, Shen RR, Cheung HW, Vazquez F, Shrestha Y, Kim SY, Giacomelli AO, Rosenbluh Joseph, Schinzel AC, Spardy NA, Barbie DA, Mermel CH, Weir BA, Garraway LA, Tamayo P, Mesirov JP, Beroukhim R, Hahn WC (2013) Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers. Cancer Discov 3:1044–1057CrossRefGoogle Scholar
- 18.Remmele W (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140Google Scholar
- 19.Gospodarowicz MK, Brierley JD, Wittekind C, et al. (eds) (2017) TNM classification of malignant tumours. Wiley, OxfordGoogle Scholar
- 24.Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, Kaufmann M, Diebold J, Arnholdt H, Müller P, Bischoff J, Harich D, Schlimok G, Gert Riethmüller RE, Klein CA (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci 100:7737–7742CrossRefGoogle Scholar
- 25.Linxweiler M, Schorr S, Schäuble N, Jung M, Linxweiler J, Langer F, Schäfers H-J, Cavalié A, Zimmermann R, Greiner M (2013) Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells. BMC Cancer 13:574CrossRefGoogle Scholar
- 28.Jackisch C, Hahm HA, Tombal B, McCloskey D, Butash K, Davidson NE, Denmeade SR (2000) Delayed micromolar elevation in intracellular calcium precedes induction of apoptosis in thapsigargin-treated breast cancer cells. Clin Cancer Res 6:2844–2850Google Scholar
- 29.Mahalingam D, Wilding G, Denmeade S, Sarantopoulas J, Cosgrove D, Cetnar J, Azad N, Bruce J, Kurman M, Allgood V, Carducci M (2016) Mipsagargin, a novel thapsigargin-based PSMA-activated prodrug: results of a first-in-man phase I clinical trial in patients with refractory, advanced or metastatic solid tumours. Br J Cancer 114:986–994CrossRefGoogle Scholar
- 32.Denmeade SR, Mhaka AM, Rosen DM, Brennen WN, Dalrymple S, Dach I, Olesen C, Gurel B, Demarzo AM, Wilding G, Carducci MA, Dionne CA, Møller JV, Nissen P, Christensen SB, Isaacs JT (2012) Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Sci Transl Med 4:14–22. https://doi.org/10.1126/scitranslmed.3003886 CrossRefGoogle Scholar
- 33.Fumagalli F, Noack J, Bergmann TJ, Cebollero E, Pisoni GB, Fasana E, Fregno I, Galli C, Loi M, Soldà T, D’Antuono R, Raimondi A, Jung M, Melnyk A, Schorr S, Schreiber A, Simonelli L, Varani L, Wilson-Zbinden C, Zerbe O, Hofmann K, Peter M, Quadroni M, Zimmermann R, Molinari M (2016) Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery. Nat Cell Biol 18:1173–1184CrossRefGoogle Scholar