Expression of RET is Associated with Oestrogen Receptor Expression but Lacks Prognostic Significance in Breast Cancer

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2019 Jan 10

PMID 30621641

Citations 17

Authors

Robert Mechera

Savas D Soysal

Salvatore Piscuoglio

Charlotte K Y Ng

Jasmin Zeindler

Edin Mujagic

Silvio Daster

Philippe Glauser

Henry Hoffmann

Ergin Kilic

Raoul A Droeser

Walter P Weber

Simone Muenst

Affiliations

Soon will be listed here.

Abstract

Background: The Rearranged during Transfection (RET) protein is overexpressed in a subset of Estrogen Receptor (ER) positive breast cancer, with both signalling pathways functionally interacting. This cross-talk plays a pivotal role in the resistance of breast cancer cells to anti-endocrine therapies, and RET expression is assumed to correlate with poor prognosis based on findings in small patient cohorts. The aim of our study was to investigate the impact of RET expression on patient outcome in human breast cancer.

Methods: We performed an immunohistochemical analysis of RET protein expression on a tissue microarray encompassing 990 breast cancer patients and correlated its expression with clinicopathological parameters and survival data.

Results: Expression of RET was detected in 409 out of 990 cases (41.3%). RET and ER expression significantly correlated (p < 0.0001). The Luminal B HER2-positive subtype showed the highest expression rate (48.9%). In univariate and multivariate survival analyses, RET expression had no impact on overall survival.

Conclusion: We confirmed the co-expression of RET and ER, but we did not find RET expression to be an independent prognostic factor in human breast cancer. Clinical trials with newly developed RET inhibitors are needed to evaluate if RET inhibition has a beneficial impact on patient survival in ER positive breast cancer.

Citing Articles

Case report: Eczematous adverse drug reaction after selpercatinib treatment.

Li B, Cao P, Xu W, Zhang L Front Oncol. 2025; 14():1475541.

PMID: 39777333 PMC: 11703860. DOI: 10.3389/fonc.2024.1475541.

REThinking the role of the RET oncogene in breast cancer.

Di Grazia G, Conti C, Nucera S, Motta G, Martorana F, Stella S Front Oncol. 2024; 14:1427228.

PMID: 39211557 PMC: 11358597. DOI: 10.3389/fonc.2024.1427228.

The potential of lenvatinib in breast cancer therapy.

Shang Y, Liu T, Wang W Med Oncol. 2024; 41(9):233.

PMID: 39172293 DOI: 10.1007/s12032-024-02477-4.

Loss of Hormone Receptor Expression after Exposure to Fluid Shear Stress in Breast Cancer Cell Lines.

Cuccia J, Ortega Quesada B, Littlefield E, Ham A, Burow M, Melvin A Int J Mol Sci. 2024; 25(13).

PMID: 39000231 PMC: 11240898. DOI: 10.3390/ijms25137119.

RET overexpression leads to increased brain metastatic competency in luminal breast cancer.

Jagust P, Powell A, Ola M, Watson L, de Pablos-Aragoneses A, Garcia-Gomez P J Natl Cancer Inst. 2024; 116(10):1632-1644.

PMID: 38852945 PMC: 11461165. DOI: 10.1093/jnci/djae091.

References

Mizuno T, Iwamoto K, Kyoizumi S, Nagamura H, Shinohara T, Koyama K . Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene. 2000; 19(3):438-43. DOI: 10.1038/sj.onc.1203343. View

Bubendorf L, Nocito A, Moch H, Sauter G . Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. J Pathol. 2001; 195(1):72-9. DOI: 10.1002/path.893. View

Iwahashi N, Murakami H, Nimura Y, Takahashi M . Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways. Biochem Biophys Res Commun. 2002; 294(3):642-9. DOI: 10.1016/S0006-291X(02)00528-4. View

Ali S, Coombes R . Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2003; 2(2):101-12. DOI: 10.1038/nrc721. View

Ichihara M, Murakumo Y, Takahashi M . RET and neuroendocrine tumors. Cancer Lett. 2004; 204(2):197-211. DOI: 10.1016/S0304-3835(03)00456-7. View

Tapia C, Schraml P, Simon R, Al-Kuraya K, Maurer R, Mirlacher M . HER2 analysis in breast cancer: reduced immunoreactivity in FISH non-informative cancer biopsies. Int J Oncol. 2004; 25(6):1551-7. View

Modi S, Seidman A, Dickler M, Moasser M, DAndrea G, Moynahan M . A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer. Breast Cancer Res Treat. 2005; 90(2):157-63. DOI: 10.1007/s10549-004-3974-0. View

Ito Y, Okada Y, Sato M, Sawai H, Funahashi H, Murase T . Expression of glial cell line-derived neurotrophic factor family members and their receptors in pancreatic cancers. Surgery. 2005; 138(4):788-94. DOI: 10.1016/j.surg.2005.07.007. View

Sawai H, Okada Y, Kazanjian K, Kim J, Hasan S, Hines O . The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005; 65(24):11536-44. DOI: 10.1158/0008-5472.CAN-05-2843. View

10.

Dowsett M, Houghton J, Iden C, Salter J, Farndon J, AHern R . Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol. 2006; 17(5):818-26. DOI: 10.1093/annonc/mdl016. View

11.

Reis-Filho J, Pinheiro C, Lambros M, Milanezi F, Carvalho S, Savage K . EGFR amplification and lack of activating mutations in metaplastic breast carcinomas. J Pathol. 2006; 209(4):445-53. DOI: 10.1002/path.2004. View

12.

Reis-Filho J, Simpson P, Turner N, Lambros M, Jones C, Mackay A . FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res. 2006; 12(22):6652-62. DOI: 10.1158/1078-0432.CCR-06-1164. View

13.

Tozlu S, Girault I, Vacher S, Vendrell J, Andrieu C, Spyratos F . Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr Relat Cancer. 2006; 13(4):1109-20. DOI: 10.1677/erc.1.01120. View

14.

Thomas R, Baker A, DeBiasi R, Winckler W, LaFramboise T, Lin W . High-throughput oncogene mutation profiling in human cancer. Nat Genet. 2007; 39(3):347-51. DOI: 10.1038/ng1975. View

15.

Esseghir S, Todd S, Hunt T, Poulsom R, Plaza-Menacho I, Reis-Filho J . A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer Res. 2007; 67(24):11732-41. DOI: 10.1158/0008-5472.CAN-07-2343. View

16.

Boulay A, Breuleux M, Stephan C, Fux C, Brisken C, Fiche M . The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer. Cancer Res. 2008; 68(10):3743-51. DOI: 10.1158/0008-5472.CAN-07-5100. View

17.

Cristofanilli M, Morandi P, Krishnamurthy S, Reuben J, Lee B, Francis D . Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-Kit or PDGFR-beta: clinical activity and biological correlations. Ann Oncol. 2008; 19(10):1713-9. PMC: 2735063. DOI: 10.1093/annonc/mdn352. View

18.

Zeng Q, Cheng Y, Zhu Q, Yu Z, Wu X, Huang K . The relationship between overexpression of glial cell-derived neurotrophic factor and its RET receptor with progression and prognosis of human pancreatic cancer. J Int Med Res. 2008; 36(4):656-64. DOI: 10.1177/147323000803600406. View

19.

Moreno-Aspitia A, Morton R, Hillman D, Lingle W, Rowland Jr K, Wiesenfeld M . Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracyclines or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clin Oncol. 2008; 27(1):11-5. PMC: 2645094. DOI: 10.1200/JCO.2007.15.5242. View

20.

Narita N, Tanemura A, Murali R, Scolyer R, Huang S, Arigami T . Functional RET G691S polymorphism in cutaneous malignant melanoma. Oncogene. 2009; 28(34):3058-68. PMC: 2738597. DOI: 10.1038/onc.2009.164. View