Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 1/2024

Open Access 01-12-2024 | Breast Cancer | Research

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy

Authors: Xiaoyu Jiang, Yuli Wang, Lulu Guo, Yige Wang, Tianshu Miao, Lijuan Ma, Qin Wei, Xiaoyan Lin, Jian-Hua Mao, Pengju Zhang

Published in: Breast Cancer Research | Issue 1/2024

Login to get access

Abstract

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.PubMedCrossRef
2.
Fan L, Strasser-Weippl K, Li JJ, St Louis J, Finkelstein DM, Yu KD, Chen WQ, Shao ZM, Goss PE. Breast cancer in China. Lancet Oncol. 2014;15(7):e279–289.PubMedCrossRef
3.
Nolan E, Lindeman GJ, Visvader JE. Deciphering breast cancer: from biology to the clinic. Cell. 2023;186(8):1708–28.PubMedCrossRef
4.
Kandula M, Chennaboina KK, Ys AR, Raju S. Phosphatidylinositol 3-kinase (PI3KCA) oncogene mutation analysis and gene expression profiling in primary breast cancer patients. Asian Pac J Cancer Prev. 2013;14(9):5067–72.PubMedCrossRef
5.
Rimawi MF, De Angelis C, Contreras A, Pareja F, Geyer FC, Burke KA, Herrera S, Wang T, Mayer IA, Forero A, et al. Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat. 2018;167(3):731–40.PubMedCrossRef
6.
Lai YL, Mau BL, Cheng WH, Chen HM, Chiu HH, Tzen CY. PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol. 2008;15(4):1064–9.PubMedCrossRef
7.
Wang J, Ji H, Niu X, Yin L, Wang Y, Gu Y, Li D, Zhang H, Lu M, Zhang F et al. Sodium-Dependent Glucose Transporter 1 (SGLT1) Stabled by HER2 Promotes Breast Cancer Cell Proliferation by Activation of the PI3K/Akt/mTOR Signaling Pathway in HER2 + Breast Cancer. Dis Markers 2020, 2020:6103542.
8.
Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmana J, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-Mutated breast Cancer. N Engl J Med. 2021;384(25):2394–405.PubMedPubMedCentralCrossRef
9.
Tarantino P, Morganti S, Curigliano G. Biologic therapy for advanced breast cancer: recent advances and future directions. Expert Opin Biol Ther. 2020;20(9):1009–24.PubMedCrossRef
10.
11.
Hua YQ, Zhang K, Sheng J, Ning ZY, Li Y, Shi WD, Liu LM. Fam83D promotes tumorigenesis and gemcitabine resistance of pancreatic adenocarcinoma through the Wnt/beta-catenin pathway. Life Sci. 2021;287:119205.PubMedCrossRef
12.
Wang J, Quan Y, Lv J, Gong S, Ren P. Inhibition of FAM83D displays antitumor effects in glioblastoma via down-regulation of the AKT/Wnt/beta-catenin pathway. Environ Toxicol. 2022;37(6):1343–56.ADSPubMedCrossRef
13.
Zhang Q, Yu S, Lok SIS, Wong AST, Jiao Y, Lee LTO. FAM83D promotes ovarian cancer progression and its potential application in diagnosis of invasive ovarian cancer. J Cell Mol Med. 2019;23(7):4569–81.PubMedPubMedCentralCrossRef
14.
Liao W, Liu W, Liu X, Yuan Q, Ou Y, Qi Y, Huang W, Wang Y, Huang J. Upregulation of FAM83D affects the proliferation and invasion of hepatocellular carcinoma. Oncotarget. 2015;6(27):24132–47.PubMedPubMedCentralCrossRef
15.
Cipriano R, Miskimen KL, Bryson BL, Foy CR, Bartel CA, Jackson MW. Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer. Mol Cancer Res. 2014;12(8):1156–65.PubMedPubMedCentralCrossRef
16.
Yin C, Lin X, Wang Y, Liu X, Xiao Y, Liu J, Snijders AM, Wei G, Mao JH, Zhang P. FAM83D promotes epithelial-mesenchymal transition, invasion and cisplatin resistance through regulating the AKT/mTOR pathway in non-small-cell lung cancer. Cell Oncol (Dordr). 2020;43(3):395–407.PubMedCrossRef
17.
Huang M, Ma X, Shi H, Hu L, Fan Z, Pang L, Zhu F, Yang X, Xu W, Liu B, et al. FAM83D, a microtubule-associated protein, promotes tumor growth and progression of human gastric cancer. Oncotarget. 2017;8(43):74479–93.PubMedPubMedCentralCrossRef
18.
Zhang T, Lai S, Cai Y, Huang Z, Li Y, Chen S, Zhang Z, Ye Z, Lai X, Zhai E, et al. Comprehensive Analysis and identification of prognostic biomarkers and therapeutic targets among FAM83 family members for gastric Cancer. Front Cell Dev Biol. 2021;9:719613.PubMedPubMedCentralCrossRef
19.
Mu Y, Zou H, Chen B, Fan Y, Luo S. FAM83D knockdown regulates proliferation, migration and invasion of colorectal cancer through inhibiting FBXW7/Notch-1 signalling pathway. Biomed Pharmacother. 2017;90:548–54.PubMedCrossRef
20.
Meng T, Tong Z, Yang MY, Zhang Y, Liu Y, Wang ZZ, Zhu LX, Wu J. Immune implication of FAM83D gene in hepatocellular carcinoma. Bioengineered. 2021;12(1):3578–92.PubMedPubMedCentralCrossRef
21.
Lin S, Du J, Hao J, Luo X, Wu H, Zhang H, Zhao X, Xu L, Wang B. Identification of prognostic biomarkers among FAM83 family genes in Human Ovarian Cancer through Bioinformatic Analysis and Experimental Verification. Cancer Manag Res. 2021;13:8611–27.PubMedPubMedCentralCrossRef
22.
Wang Z, Liu Y, Zhang P, Zhang W, Wang W, Curr K, Wei G, Mao JH. FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7. Oncotarget. 2013;4(12):2476–86.PubMedPubMedCentralCrossRef
23.
24.
25.
Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, Cepeda D, Fiegl H, Dafou D, Marth C, et al. FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 2007;67(19):9006–12.PubMedCrossRef
26.
Akhoondi S, Lindstrom L, Widschwendter M, Corcoran M, Bergh J, Spruck C, Grander D, Sangfelt O. Inactivation of FBXW7/hCDC4-beta expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer. Breast Cancer Res. 2010;12(6):R105.PubMedPubMedCentralCrossRef
27.
Shen W, Zhou Q, Peng C, Li J, Yuan Q, Zhu H, Zhao M, Jiang X, Liu W, Ren C. FBXW7 and the hallmarks of Cancer: underlying mechanisms and prospective strategies. Front Oncol. 2022;12:880077.PubMedPubMedCentralCrossRef
28.
Cheng TC, Tu SH, Chen LC, Chen MY, Chen WY, Lin YK, Ho CT, Lin SY, Wu CH, Ho YS. Down-regulation of α-L-fucosidase 1 expression confers inferior survival for triple-negative breast cancer patients by modulating the glycosylation status of the tumor cell surface. Oncotarget. 2015;6(25):21283–300.PubMedPubMedCentralCrossRef
29.
Ezawa I, Sawai Y, Kawase T, Okabe A, Tsutsumi S, Ichikawa H, Kobayashi Y, Tashiro F, Namiki H, Kondo T, et al. Novel p53 target gene FUCA1 encodes a fucosidase and regulates growth and survival of cancer cells. Cancer Sci. 2016;107(6):734–45.PubMedPubMedCentralCrossRef
30.
Baudot AD, Crighton D, O’Prey J, Somers J, Sierra Gonzalez P, Ryan KM. p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death. Cell Cycle (Georgetown Tex). 2016;15(17):2299–308.PubMedCrossRef
31.
Vecchio G, Parascandolo A, Allocca C, Ugolini C, Basolo F, Moracci M, Strazzulli A, Cobucci-Ponzano B, Laukkanen MO, Castellone MD, et al. Human a-L-fucosidase-1 attenuates the invasive properties of thyroid cancer. Oncotarget. 2017;8(16):27075–92.PubMedPubMedCentralCrossRef
32.
Xu L, Li Z, Song S, Chen Q, Mo L, Wang C, Fan W, Yan Y, Tong X, Yan H. Downregulation of α-l-fucosidase 1 suppresses glioma progression by enhancing autophagy and inhibiting macrophage infiltration. Cancer Sci. 2020;111(7):2284–96.PubMedPubMedCentralCrossRef
33.
Liang Y, Zhang H, Song X, Yang Q. Metastatic heterogeneity of breast cancer: molecular mechanism and potential therapeutic targets. Semin Cancer Biol. 2020;60:14–27.PubMedCrossRef
34.
Turner KM, Yeo SK, Holm TM, Shaughnessy E, Guan JL. Heterogeneity within molecular subtypes of breast cancer. Am J Physiol Cell Physiol. 2021;321(2):C343–54.PubMedPubMedCentralCrossRef
35.
Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, et al. The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001;414(6866):865–71.ADSPubMedCrossRef
36.
Yang XX, Ma M, Sang MX, Zhang XY, Zou NY, Zhu SC. Knockdown of FAM83D enhances radiosensitivity in coordination with irradiation by inhibiting EMT via the Akt/GSK-3beta/Snail signaling pathway in human esophageal Cancer cells. Onco Targets Ther. 2020;13:4665–78.PubMedPubMedCentralCrossRef
37.
Li J, Li Z, Gao Y, Zhao H, Guo J, Liu Z, Yin C, Zhao X, Yue W. Integrating single-cell RNA sequencing and prognostic model revealed the carcinogenicity and clinical significance of FAM83D in ovarian cancer. Front Oncol. 2022;12:1055648.PubMedPubMedCentralCrossRef
38.
Wang F, Zhang S, Wei Y, Chen H, Jiao Z, Li Y. Upregulation of family with sequence similarity 83 member D expression enhances cell proliferation and motility via activation of Wnt/beta-catenin signaling and predicts poor prognosis in gastric cancer. Cancer Manag Res. 2019;11:6775–91.PubMedPubMedCentralCrossRef
39.
Zhu H, Diao S, Lim V, Hu L, Hu J. FAM83D inhibits autophagy and promotes proliferation and invasion of ovarian cancer cells via PI3K/AKT/mTOR pathway. Acta Biochim Biophys Sin (Shanghai). 2019;51(5):509–16.PubMedCrossRef
40.
Zhao T, Wang M, Zhao X, Weng S, Qian K, Shi K, Gu Y, Ying W, Qian X, Zhang Y. YTHDF2 inhibits the Migration and Invasion of Lung Adenocarcinoma by negatively regulating the FAM83D-TGFbeta1-SMAD2/3 pathway. Front Oncol. 2022;12:763341.PubMedPubMedCentralCrossRef
41.
Wang D, Han S, Peng R, Wang X, Yang XX, Yang RJ, Jiao CY, Ding D, Ji GW, Li XC. FAM83D activates the MEK/ERK signaling pathway and promotes cell proliferation in hepatocellular carcinoma. Biochem Biophys Res Commun. 2015;458(2):313–20.PubMedCrossRef
42.
Nie J, Lu L, Du C, Gao X. FAM83D promotes the proliferation and migration of hepatocellular carcinoma cells by inhibiting the FBXW7/MCL1 pathway. Transl Cancer Res. 2022;11(10):3790–802.PubMedPubMedCentralCrossRef
43.
Zhan P, Wang Y, Zhao S, Liu C, Wang Y, Wen M, Mao JH, Wei G, Zhang P. FBXW7 negatively regulates ENO1 expression and function in colorectal cancer. Lab Invest. 2015;95(9):995–1004.PubMedPubMedCentralCrossRef
44.
Xiao Y, Yin C, Wang Y, Lv H, Wang W, Huang Y, Perez-Losada J, Snijders AM, Mao JH, Zhang P. FBXW7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy. Mol Oncol. 2018;12(6):883–95.PubMedPubMedCentralCrossRef
45.
Wang W, Wang M, Xiao Y, Wang Y, Ma L, Guo L, Wu X, Lin X, Zhang P. USP35 mitigates endoplasmic reticulum stress-induced apoptosis by stabilizing RRBP1 in non-small cell lung cancer. Mol Oncol. 2022;16(7):1572–90.PubMedCrossRef
46.
Jin J, Qiu S, Wang P, Liang X, Huang F, Wu H, Zhang B, Zhang W, Tian X, Xu R, et al. Cardamonin inhibits breast cancer growth by repressing HIF-1alpha-dependent metabolic reprogramming. J Exp Clin Cancer Res. 2019;38(1):377.PubMedPubMedCentralCrossRef
47.
Liu S, Sun Y, Hou Y, Yang L, Wan X, Qin Y, Liu Y, Wang R, Zhu P, Teng Y, et al. A novel lncRNA ROPM-mediated lipid metabolism governs breast cancer stem cell properties. J Hematol Oncol. 2021;14(1):178.PubMedPubMedCentralCrossRef
48.
Wang Y, Zhang P, Wang Y, Zhan P, Liu C, Mao JH, Wei G. Distinct interactions of EBP1 isoforms with FBXW7 elicits different functions in Cancer. Cancer Res. 2017;77(8):1983–96.PubMedPubMedCentralCrossRef
Metadata
Title
The FBXW7-binding sites on FAM83D are potential targets for cancer therapy
Authors
Xiaoyu Jiang
Yuli Wang
Lulu Guo
Yige Wang
Tianshu Miao
Lijuan Ma
Qin Wei
Xiaoyan Lin
Jian-Hua Mao
Pengju Zhang
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2024
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-024-01795-9

Other articles of this Issue 1/2024

Breast Cancer Research 1/2024 Go to the issue

Research

Factors associated with overall survival in breast cancer patients with leptomeningeal disease (LMD): a single institutional retrospective review

Research

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea

Review

Reporting on patient’s body mass index (BMI) in recent clinical trials for patients with breast cancer: a systematic review

Research

Paradoxical cancer cell proliferation after FGFR inhibition through decreased p21 signaling in FGFR1-amplified breast cancer cells

Research

Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential

Research

Clinically relevant gene signatures provide independent prognostic information in older breast cancer patients
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits