Prognostic implication and oncogenic role of DDIT3 in breast cancer

Abstract

Although DNA damage-inducible transcript 3 (DDIT3) has been identified as a novel gene associated with breast cancer, its clinical significance, biological function, and underlying mechanisms remain unclear. By integrating immunohistochemistry with data from The Cancer Genome Atlas (TCGA), we discovered that elevated levels of DDIT3 Messenger RNA and protein expression are significantly associated with poor prognosis in patients with breast cancer. Functional assays and preliminary mechanistic studies reveal that DDIT3 may promote breast cancer cell proliferation and metastasis, potentially by downregulating activating transcription factor-2.

Keywords

Breast cancer / DDIT3 / Prognosis / Oncogene

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. doi: 10.3322/caac.21834

[2] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. doi: 10.3322/caac.21660

[3] Wang X, Xia C, Wang Y, et al. Landscape of young breast cancer under 35 years in China over the past decades: A multicentre retrospective cohort study (YBCC-Catts study). EClinicalMedicine. 2023; 64:102243. doi: 10.1016/j.eclinm.2023.102243

[4] Chinese Society of Clinical Oncology, Experts Committee on Breast Cancer, China Anti-Cancer Association, the Society of Breast Cancer, Chinese Medical Association, Chinese Society of Breast Surgery. [Expert consensus on the diagnosis and treatment of young breast cancer in China (2022 Edition)]. Zhonghua Yi Xue Za Zhi. 2023; 103(6):387-403. doi: 10.3760/cma.j.cn112137-20220907-01895

[5] Mokhtary A, Karakatsanis A, Valachis A. Mammographic density changes over time and breast cancer risk: A systematic review and meta-analysis. Cancers (Basel). 2021; 13(19):4805. doi: 10.3390/cancers13194805

[6] Hussein H, Abbas E, Keshavarzi S, et al. Supplemental breast cancer screening in women with dense breasts and negative mammography: A systematic review and meta-analysis. Radiology. 2023; 306(3):e221785. doi: 10.1148/radiol.221785

[7] Glechner A, Wagner G, Mitus JW, et al. Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk. Cochrane Database Syst Rev. 2023; 3(3):CD009632. doi: 10.1002/14651858.CD009632.pub3

[8] Gameel AM, Talaat RM, Sakr MA, Selim MA, Abo Alil DFA, Elkhouly EA. Circulating tumor DNA in Egyptian women with breast Cancer: A marker for detection of primary cases and early prediction of recurrence. Clin Chim Acta. 2024; 562:119878. doi: 10.1016/j.cca.2024.119878

[9] Li X, Dai D, Chen B, Tang H, Xie X, Wei W. Clinicopathological and prognostic significance of cancer antigen 15-3 and carcinoembryonic antigen in breast cancer: A meta-analysis including 12,993 patients. Dis Markers. 2018; 2018:9863092. doi: 10.1155/2018/9863092

[10] Osman A, Lindén M, Österlund T, et al. Identification of genomic binding sites and direct target genes for the transcription factor DDIT3/CHOP. Exp Cell Res. 2023; 422(1):113418. doi: 10.1016/j.yexcr.2022.113418

[11] Luo HH, Ren WY, Ye AH, et al. DDIT3 switches osteogenic potential of BMP9 to lipogenic by attenuating Wnt/β- catenin signaling via up-regulating DKK1 in mesenchymal stem cells. Aging (Albany NY). 2024; 16(18):12543-12558. doi: 10.18632/aging.206091

[12] Chen P, Chen C, Hu M, et al. S-allyl-L-cysteine protects hepatocytes from indomethacin-induced apoptosis by attenuating endoplasmic reticulum stress. FEBS Open Bio. 2020; 10(9):1900-1911. doi: 10.1002/2211-5463.12945

[13] Berastegui N, Ainciburu M, Romero JP, et al. The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes. Nat Commun. 2022; 13(1):7619. doi: 10.1038/s41467-022-35192-7

[14] Wang S, Zhang M, Liu Z, et al. Relationship between CHOP/ GADD153 and unstable human carotid atherosclerotic plaque. Br J Neurosurg. 2017; 31(6):648-652.doi: 10.1080/02688697.2017.1327016

[15] Scapa JV, Cloutier JM, Raghavan SS, Peters-Schulze G, Varma S, Charville GW. DDIT3 immunohistochemistry is a useful tool for the diagnosis of myxoid liposarcoma. Am J Surg Pathol. 2021; 45(2):230-239. doi: 10.1097/PAS.0000000000001564

[16] Zhan W, Chen L, Liu H, et al. Pcsk6 deficiency promotes cardiomyocyte senescence by modulating ddit3-mediated ER stress. Genes (Basel). 2022; 13(4):711. doi: 10.3390/genes13040711

[17] Tyler R, Wanigasooriya K, Taniere P, et al. A review of retroperitoneal liposarcoma genomics. Cancer Treat Rev. 2020; 86:102013. doi: 10.1016/j.ctrv.2020.102013

[18] De Vreeze RS, De Jong D, Tielen IH, et al. Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: An immunohistochemical and molecular biological analysis. Mod Pathol. 2009; 22(2):223-231. doi: 10.1038/modpathol.2008.164

[19] Garcia-Ortega DY. Comprehensive treatment strategy for improving surgical resection rate of retroperitoneal sarcomas: A histology-specific approach narrative review. Front Oncol. 2024; 14:1432900. doi: 10.3389/fonc.2024.1432900

[20] Yu Q, Zhao J, Yang A, Li X. MLLT6/ATF2 axis restrains breast cancer progression by driving DDIT3/4 expression. Mol Cancer Res. 2024; 22(9):796-811. doi: 10.1158/1541-7786.MCR-23-0648

[21] Zhang L, Wang Q, Wang L, et al. OSskcm: An online survival analysis webserver for skin cutaneous melanoma based on 1085 transcriptomic profiles. Cancer Cell Int. 2020; 20:176. doi: 10.1186/s12935-020-01262-3

[22] Lee CY, Lee MG, Choi KC, Kang HM, Chang YS. Clinical significance of GADD153 expression in stage I non-small cell lung cancer. Oncol Lett. 2012; 4(3):408-412. doi: 10.3892/ol.2012.768

[23] Zhang X, Zhou T, Li W, Zhang T, Che N, Zu G. Clinicopathological and prognostic significance of C/EBP homologous protein (CHOP) in advanced gastric cancer. Pathol Res Pract. 2018; 214(8):1105-1109. doi: 10.1016/j.prp.2018.06.005

[24] Lin H, Liu S, Gao W, Liu H. DDIT3 modulates cancer stemness in gastric cancer by directly regulating CEBPβ. J Pharm Pharmacol. 2020; 72(6):807-815. doi: 10.1111/jphp.13243

[25] Jung KJ, Min KJ, Bae JH, Kwon TK. Carnosic acid sensitized TRAIL-mediated apoptosis through down-regulation of c-FLIP and Bcl-2 expression at the post-translational levels and CHOP-dependent up-regulation of DR5 Bim and PUMA expression in human carcinoma caki cells. Oncotarget. 2015; 6(3):1556-1568. doi: 10.18632/oncotarget.2727

[26] Li T, Su L, Lei Y, Liu X, Zhang Y, Liu X. DDIT3 and KAT2A proteins regulate TNFRSF10A and TNFRSF10B expression in endoplasmic reticulum stress-mediated apoptosis in human lung cancer cells. J Biol Chem. 2015; 290(17):11108-11118. doi: 10.1074/jbc.M115.645333

[27] Yang C, Xu X, Dong X, et al. DDIT3/CHOP promotes autophagy in chondrocytes via SIRT1-AKT pathway. Biochim Biophys Acta Mol Cell Res. 2021; 1868(9): 119074. doi: 10.1016/j.bbamcr.2021.119074

[28] Mukherjee S, Bandyopadhyay SS. Phorbol-12-myristate-13-acetate (PMA) mediated transcriptional regulation of Oncostatin-M. Cytokine. 2016; 88:209-213. doi: 10.1016/j.cyto.2016.09.006

[29] Park JS, Lim CJ, Bang OS, Kim NS. Ethanolic extract of Descurainia sophia seeds sensitizes A 549 human lung cancer cells to TRAIL cytotoxicity by upregulating death receptors. BMC Complement Altern Med. 2016; 16:115. doi: 10.1186/s12906-016-1094-0

[30] Li M, Thorne RF, Shi R, et al. DDIT3 directs a dual mechanism to balance glycolysis and oxidative phosphorylation during glutamine deprivation. Adv Sci (Weinh). 2021; 8(11):e2003732. doi: 10.1002/advs.202003732

[31] Lopez-Bergami P, Lau E, Ronai Z. Emerging roles of ATF2 and the dynamic AP 1 network in cancer. Nat Rev Cancer. 2010; 10(1):65-76. doi: 10.1038/nrc2681

[32] Giannoudis A, Malki MI, Rudraraju B, et al. Activating transcription factor-2 (ATF2) is a key determinant of resistance to endocrine treatment in an in vitro model of breast cancer. Breast Cancer Res. 2020; 22(1):126. doi: 10.1186/s13058-020-01359-7