P53 Status Influences the Anti-proliferative Effect Induced by IFITM1 Inhibition in Estrogen Receptor-positive Breast Cancer Cells

Overview

Journal Cancer Genomics Proteomics

Specialties Biochemistry
Genetics
Oncology

Date 2024 Aug 27

PMID 39191497

Authors

DER Sheng Sun

Jung-Sook Yoon

Yong-Seok Kim

Hye Sung Won

Affiliations

Soon will be listed here.

Abstract

Background/aim: Interferon-induced trans-membrane protein 1 (IFITM1) is known to be involved in breast cancer progression. We aimed to investigate its role in estrogen receptor (ER)-positive breast cancer cells with wild-type p53 and tamoxifen-resistant breast cancer cells.

Materials And Methods: The ER-positive breast cancer cell lines, MCF-7 with wild-type p53 and T47D with mutant p53, were used. We established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen.

Results: IFITM1 inhibition in MCF-7 cells significantly decreased cell growth and migration. MCF-7 cells with suppression of IFITM1 using siRNA or ruxolitinib showed reduced cell viability after tamoxifen treatment compared with that in the control MCF-7 cells. Unexpectedly, mRNA and protein levels of IFITM1 were decreased in TamR cells compared with those in MCF-7 cells. TamR cells with suppression of IFITM1 using siRNA or ruxolitinib showed no change in cell viability after treatment with tamoxifen. P53 knockdown using siRNA reduced the mRNA levels of IRF9 and increased mRNA and protein levels of SOCS3 in MCF-7 cells, suggesting that loss or mutation of p53 can affect the induction of IFITM1 via the JAK/STAT signaling pathway in breast cancer. Furthermore, MCF-7 cells with p53 knockdown using siRNA showed no decrease in cell viability after tamoxifen treatment or IFITM1 inhibition, indicating that p53 status may be important for cell death after tamoxifen treatment or IFITM1 inhibition.

Conclusion: IFITM1 inhibition may enhance the sensitivity to tamoxifen based on p53-dependent enhancement of IFN signaling in wild-type p53, ER-positive breast cancer cells.

References

Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A . Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol. 2011; 31(5):980-5. DOI: 10.1161/ATVBAHA.110.207464. View

Makhlin I, McAndrew N, Wileyto E, Clark A, Holmes R, Bottalico L . Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer. NPJ Breast Cancer. 2022; 8(1):122. PMC: 9652412. DOI: 10.1038/s41523-022-00487-x. View

Fu X, De Angelis C, Schiff R . Interferon Signaling in Estrogen Receptor-positive Breast Cancer: A Revitalized Topic. Endocrinology. 2021; 163(1). DOI: 10.1210/endocr/bqab235. View

Friedlova N, Zavadil Kokas F, Hupp T, Vojtesek B, Nekulova M . IFITM protein regulation and functions: Far beyond the fight against viruses. Front Immunol. 2022; 13:1042368. PMC: 9716219. DOI: 10.3389/fimmu.2022.1042368. View

Espin-Rivera A, Meza-Aparicio F, Reyna-Flores F, Burguete-Garcia A, Guzman-Olea E, Bermudez-Morales V . Interferon-tau (IFN-τ) Has Antiproliferative Effects, Induces Apoptosis, and Inhibits Tumor Growth in a Triple-negative Breast Cancer Murine Tumor Model. In Vivo. 2023; 37(6):2517-2523. PMC: 10621435. DOI: 10.21873/invivo.13359. View

Lim L, Vidnovic N, Ellisen L, Leong C . Mutant p53 mediates survival of breast cancer cells. Br J Cancer. 2009; 101(9):1606-12. PMC: 2778523. DOI: 10.1038/sj.bjc.6605335. View

Kim G, Ouzounova M, Quraishi A, Davis A, Tawakkol N, Clouthier S . SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene. 2014; 34(6):671-80. PMC: 4285772. DOI: 10.1038/onc.2014.4. View

Escher T, Lui A, Geanes E, Walter K, Tawfik O, Hagan C . Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor-Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis. Mol Cancer Res. 2019; 17(5):1180-1194. PMC: 6497545. DOI: 10.1158/1541-7786.MCR-18-0916. View

Munoz-Fontela C, Mandinova A, Aaronson S, Lee S . Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol. 2016; 16(12):741-750. PMC: 5325695. DOI: 10.1038/nri.2016.99. View

10.

Yang G, Xu Y, Chen X, Hu G . IFITM1 plays an essential role in the antiproliferative action of interferon-gamma. Oncogene. 2006; 26(4):594-603. DOI: 10.1038/sj.onc.1209807. View

11.

Munoz-Fontela C, Macip S, Martinez-Sobrido L, Brown L, Ashour J, Garcia-Sastre A . Transcriptional role of p53 in interferon-mediated antiviral immunity. J Exp Med. 2008; 205(8):1929-38. PMC: 2525597. DOI: 10.1084/jem.20080383. View

12.

Ogony J, Choi H, Lui A, Cristofanilli M, Lewis-Wambi J . Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res. 2016; 18(1):25. PMC: 4761146. DOI: 10.1186/s13058-016-0683-7. View

13.

Lu J, McEachern D, Li S, Ellis M, Wang S . Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer. Mol Cancer Ther. 2016; 15(12):2887-2893. PMC: 5367629. DOI: 10.1158/1535-7163.MCT-16-0028. View

14.

Fernandez-Cuesta L, Anaganti S, Hainaut P, Olivier M . p53 status influences response to tamoxifen but not to fulvestrant in breast cancer cell lines. Int J Cancer. 2010; 128(8):1813-21. DOI: 10.1002/ijc.25512. View

15.

Lasut-Szyszka B, Rusin M . The Wheel of p53 Helps to Drive the Immune System. Int J Mol Sci. 2023; 24(8). PMC: 10143509. DOI: 10.3390/ijms24087645. View

16.

Fu J, Chen R, Zhang Z, Zhao J, Xia T . An inflammatory-related genes signature based model for prognosis prediction in breast cancer. Oncol Res. 2023; 31(2):157-167. PMC: 10207981. DOI: 10.32604/or.2023.027972. View

17.

Belachew E, Sewasew D . Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer. Front Endocrinol (Lausanne). 2021; 12:599586. PMC: 8030661. DOI: 10.3389/fendo.2021.599586. View

18.

. Comprehensive molecular portraits of human breast tumours. Nature. 2012; 490(7418):61-70. PMC: 3465532. DOI: 10.1038/nature11412. View

19.

Hu X, Li J, Fu M, Zhao X, Wang W . The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021; 6(1):402. PMC: 8617206. DOI: 10.1038/s41392-021-00791-1. View

20.

Berns E, Foekens J, Vossen R, Look M, Devilee P, Henzen-Logmans S . Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. Cancer Res. 2000; 60(8):2155-62. View