Table Info

Table 1.

E3-Ub ligases types

Main types of E3 ligases	Characteristics	Action mode
RING E3 ligases	Contains a RING domain or U-box domain	Ub is transferred in one step from the E2-conjugating enzyme to the substrate
Homologous to the HECT E3 ligases	Subfamilies: 1. RCC1-like domains; 2. tryptophan-tryptophan domains; 3. ligases lacking these domains	Ub is transferred in two steps: these ligases first transfer Ub from the E2-conjugating enzyme to themselves and subsequently to the substrate
RBR E3 ligases	Contain an IBR which separates two predicted RING domains (RING1 and RING2)

RCC1: regulator of chromosome condensation 1; RBR: RING-in-between-RING; HECT: E6AP carboxyl terminus; IBR: in between ring

Declarations

Acknowledgments

We thank Alfonso Ramos Flores for technical help with this manuscript.

Author contributions

ACTC designed the research, integrated the information, and wrote the manuscript. JZC helped in the research and the integration of information and improving the manuscript. JORJ helped in the manuscript and prepared the figures. ARO helped in the research.

Conflicts of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Bernassola F, Karin M, Ciechanover A, Melino G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell. 2008;14:10–21. [DOI] [PubMed]

Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem. 2009;78:399–434. [DOI] [PubMed]

Metzger MB, Pruneda JN, Klevit RE, Weissman AM. RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. Biochim Biophys Acta. 2014;1843:47–60. [DOI] [PubMed] [PMC]

Sahu I, Glickman MH. Proteasome in action: substrate degradation by the 26S proteasome. Biochem Soc Trans. 2021;49:629–44. [DOI] [PubMed] [PMC]

Woelk T, Sigismund S, Penengo L, Polo S. The ubiquitination code: a signalling problem. Cell Div. 2007;2:11. [DOI] [PubMed] [PMC]

Morreale FE, Walden H. Types of ubiquitin ligases. Cell. 2016;165:248–e1. [DOI] [PubMed]

Scheffner M, Kumar S. Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects. Biochim Biophys Acta. 2014;1843:61–74. [DOI] [PubMed]

Zheng N, Shabek N. Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem. 2017;86:129–57. [DOI] [PubMed]

D’Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther. 2015;147:32–54. [DOI] [PubMed]

10.

Helzer KT, Hooper C, Miyamoto S, Alarid ET. Ubiquitylation of nuclear receptors: new linkages and therapeutic implications. J Mol Endocrinol. 2015;54:R151–67. [DOI] [PubMed] [PMC]

11.

Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem. 2017;86:159–92. [DOI] [PubMed]

12.

Sadowski M, Suryadinata R, Tan AR, Roesley SN, Sarcevic B. Protein monoubiquitination and polyubiquitination generate structural diversity to control distinct biological processes. IUBMB Life. 2012;64:136–42. [DOI] [PubMed]

13.

Di Fiore PP, Polo S, Hofmann K. When ubiquitin meets ubiquitin receptors: a signalling connection. Nat Rev Mol Cell Biol. 2003;4:491–7. [DOI] [PubMed]

14.

Wang X, Terpstra EJ. Ubiquitin receptors and protein quality control. J Mol Cell Cardiol. 2013;55:73–84. [DOI] [PubMed] [PMC]

15.

Dikic I, Wakatsuki S, Walters KJ. Ubiquitin-binding domains-from structures to functions. Nat Rev Mol Cell Biol. 2009;10:659–71. [DOI] [PubMed] [PMC]

16.

Husnjak K, Dikic I. Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem. 2012;81:291–322. [DOI] [PubMed]

17.

Bonacci T, Audebert S, Camoin L, Baudelet E, Iovanna JL, Soubeyran P. Regulation of NUB1 activity through non-proteolytic Mdm2-mediated ubiquitination. PLoS One. 2017;12:e0169988. [DOI] [PubMed] [PMC]

18.

Fei C, Li Z, Li C, Chen Y, Chen Z, He X, et al. Smurf1-mediated Lys29-linked nonproteolytic polyubiquitination of axin negatively regulates Wnt/β-catenin signaling. Mol Cell Biol. 2013;33:4095–105. [DOI] [PubMed] [PMC]

19.

Hurley JH, Lee S, Prag G. Ubiquitin-binding domains. Biochem J. 2006;399:361–72. [DOI] [PubMed] [PMC]

20.

Kuslansky Y, Sominsky S, Jackman A, Gamell C, Monahan BJ, Haupt Y, et al. Ubiquitin ligase E6AP mediates nonproteolytic polyubiquitylation of β-catenin independent of the E6 oncoprotein. J Gen Virol. 2016;97:3313–30. [DOI] [PubMed]

21.

Scott D, Oldham NJ, Strachan J, Searle MS, Layfield R. Ubiquitin-binding domains: mechanisms of ubiquitin recognition and use as tools to investigate ubiquitin-modified proteomes. Proteomics. 2015;15:844–61. [DOI] [PubMed]

22.

Dragovich PS, Adhikari P, Blake RA, Blaquiere N, Chen J, Cheng YX, et al. Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα). Bioorg Med Chem Lett. 2020;30:126907. [DOI] [PubMed]

23.

Lin X, Xiang H, Luo G. Targeting estrogen receptor α for degradation with PROTACs: a promising approach to overcome endocrine resistance. Eur J Med Chem. 2020;206:112689. [DOI] [PubMed]

24.

Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2001;98:8554–9. [DOI] [PubMed] [PMC]

25.

Hu J, Hu B, Wang M, Xu F, Miao B, Yang CY, et al. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER). J Med Chem. 2019;62:1420–42. [DOI] [PubMed]

26.

Dai Y, Yue N, Gong J, Liu C, Li Q, Zhou J, et al. Development of cell-permeable peptide-based PROTACs targeting estrogen receptor α. Eur J Med Chem. 2020;187:111967. [DOI] [PubMed]

27.

Qi SM, Dong J, Xu ZY, Cheng XD, Zhang WD, Qin JJ. PROTAC: an effective targeted protein degradation strategy for cancer therapy. Front Pharmacol. 2021;12:692574. [DOI] [PubMed] [PMC]

28.

Pei H, Peng Y, Zhao Q, Chen Y. Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery. RSC Adv. 2019;9:16967–76. [DOI]

29.

Edmondson SD, Yang B, Fallan C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: recent progress and future challenges. Bioorg Med Chem Lett. 2019;29:1555–64. [DOI] [PubMed]

30.

Manavathi B, Samanthapudi VS, Gajulapalli VN. Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development. Front Cell Dev Biol. 2014;2:34. [DOI] [PubMed] [PMC]

31.

Pesiri V, Di Muzio E, Polticelli F, Acconcia F. Selective binding of estrogen receptor α to ubiquitin chains. IUBMB Life. 2016;68:569–77. [DOI] [PubMed]

32.

Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the st. gallen international expert consensus conference on the primary therapy of early breast cancer 2017. Ann Oncol. 2017;28:1700–12. [DOI] [PubMed] [PMC]

33.

Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95. [DOI] [PubMed] [PMC]

34.

Yi M, Huo L, Koenig KB, Mittendorf EA, Meric-Bernstam F, Kuerer HM, et al. Which threshold for ER positivity? a retrospective study based on 9639 patients. Ann Oncol. 2014;25:1004–11. [DOI] [PubMed] [PMC]

35.

Chen T, Zhang N, Moran MS, Su P, Haffty BG, Yang Q. Borderline ER-positive primary breast cancer gains no significant survival benefit from endocrine therapy: a systematic review and meta-analysis. Clin Breast Cancer. 2018;18:1–8. [DOI] [PubMed]

36.

Collins LC, Botero ML, Schnitt SJ. Bimodal frequency distribution of estrogen receptor immunohistochemical staining results in breast cancer: an analysis of 825 cases. Am J Clin Pathol. 2005;123:16–20. [DOI] [PubMed]

37.

Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M. S-palmitoylation modulates human estrogen receptor-alpha functions. Biochem Biophys Res Commun. 2004;316:878–83. [DOI] [PubMed]

38.

Pedram A, Razandi M, Deschenes RJ, Levin ER. DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol Biol Cell. 2012;23:188–99. [DOI] [PubMed] [PMC]

39.

Tecalco-Cruz AC, Pérez-Alvarado IA, Ramírez-Jarquín JO, Rocha-Zavaleta L. Nucleo-cytoplasmic transport of estrogen receptor alpha in breast cancer cells. Cell Signal. 2017;34:121–32. [DOI] [PubMed]

40.

Caligiuri I, Toffoli G, Giordano A, Rizzolio F. pRb controls estrogen receptor alpha protein stability and activity. Oncotarget. 2013;4:875–83. [DOI] [PubMed] [PMC]

41.

Kumar R, Wang RA, Mazumdar A, Talukder AH, Mandal M, Yang Z, et al. A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm. Nature. 2002;418:654–7. [DOI] [PubMed]

42.

Björnström L, Sjöberg M. Estrogen receptor-dependent activation of AP-1 via non-genomic signalling. Nucl Recept. 2004;2:3. [DOI] [PubMed] [PMC]

43.

Frasor J, Weaver A, Pradhan M, Dai Y, Miller LD, Lin CY, et al. Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res. 2009;69:8918–25. [DOI] [PubMed] [PMC]

44.

Vrtačnik P, Ostanek B, Mencej-Bedrač S, Marc J. The many faces of estrogen signaling. Biochem Med (Zagreb). 2014;24:329–42. [DOI] [PubMed] [PMC]

45.

Hah N, Murakami S, Nagari A, Danko CG, Kraus WL. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res. 2013;23:1210–23. [DOI] [PubMed] [PMC]

46.

Kumar R, Zakharov MN, Khan SH, Miki R, Jang H, Toraldo G, et al. The dynamic structure of the estrogen receptor. J Amino Acids. 2011;2011:812540. [DOI] [PubMed] [PMC]

47.

Nardulli AM, Greene GL, Shapiro DJ. Human estrogen receptor bound to an estrogen response element bends DNA. Mol Endocrinol. 1993;7:331–40. [DOI] [PubMed]

48.

Billon-Galés A, Krust A, Fontaine C, Abot A, Flouriot G, Toutain C, et al. Activation function 2 (AF2) of estrogen receptor-alpha is required for the atheroprotective action of estradiol but not to accelerate endothelial healing. Proc Natl Acad Sci U S A. 2011;108:13311–6. [DOI] [PubMed] [PMC]

49.

Métivier R, Penot G, Flouriot G, Pakdel F. Synergism between ERalpha transactivation function 1 (AF-1) and AF-2 mediated by steroid receptor coactivator protein-1: requirement for the AF-1 alpha-helical core and for a direct interaction between the N- and C-terminal domains. Mol Endocrinol. 2001;15:1953–70. [DOI] [PubMed]

50.

Smirnova NF, Fontaine C, Buscato M, Lupieri A, Vinel A, Valera MC, et al. The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells. Circ Res. 2015;117:770–8. [DOI] [PubMed] [PMC]

51.

Zwart W, de Leeuw R, Rondaij M, Neefjes J, Mancini MA, Michalides R. The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen. J Cell Sci. 2010;123(Pt 8):1253–61. [DOI] [PubMed]

52.

Fleming FJ, Hill AD, McDermott EW, O’Higgins NJ, Young LS. Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by beta-estradiol and 4-hydroxytamoxifen in human breast cancer. J Clin Endocrinol Metab. 2004;89:375–83. [DOI] [PubMed]

53.

Hah N, Kraus WL. Hormone-regulated transcriptomes: lessons learned from estrogen signaling pathways in breast cancer cells. Mol Cell Endocrinol. 2014;382:652–64. [DOI] [PubMed] [PMC]

54.

Hervouet E, Cartron PF, Jouvenot M, Delage-Mourroux R. Epigenetic regulation of estrogen signaling in breast cancer. Epigenetics. 2013;8:237–45. [DOI] [PubMed] [PMC]

55.

Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 2005;122:33–43. [DOI] [PubMed]

56.

Theodorou V, Stark R, Menon S, Carroll JS. GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility. Genome Res. 2013;23:12–22. [DOI] [PubMed] [PMC]

57.

Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2020;70:7–30. [DOI] [PubMed]

58.

Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al; American Society of Clinical Oncology; College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013. [DOI] [PubMed]

59.

Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36:2105–22. [DOI] [PubMed]

60.

Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26:6469–87. [DOI] [PubMed] [PMC]

61.

Perez EA, Reinholz MM, Hillman DW, Tenner KS, Schroeder MJ, Davidson NE, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol. 2010;28:4307–15. [DOI] [PubMed] [PMC]

62.

Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:852748. [DOI] [PubMed] [PMC]

63.

Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: review of results from 37,992 patients. Cancer Metastasis Rev. 2015;34:157–64. [DOI] [PubMed] [PMC]

64.

Howell SJ, Johnston SR, Howell A. The use ofselectiveestrogenreceptor modulators and selectiveestrogen receptor down-regulators in breast cancer. Best Pract Res Clin Endocrinol Metab. 2004;18:47–66. [DOI] [PubMed]

65.

Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233–47. [DOI] [PubMed] [PMC]

66.

Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1–24. [DOI] [PubMed]

67.

Osborne CK, Wakeling A, Nicholson RI. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer. 2004;90 Suppl 1:S2–6. [DOI] [PubMed] [PMC]

68.

Wardell SE, Marks JR, McDonnell DP. The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy. Biochem Pharmacol. 2011;82:122–30. [DOI] [PubMed] [PMC]

69.

AlFakeeh A, Brezden-Masley C. Overcoming endocrine resistance in hormone receptor-positive breast cancer. Curr Oncol. 2018;25 Suppl 1:S18–27. [DOI] [PubMed] [PMC]

70.

Acconcia F, Kumar R. Signaling regulation of genomic and nongenomic functions of estrogen receptors. Cancer Lett. 2006;238:1–14. [DOI] [PubMed]

71.

Angus L, Beije N, Jager A, Martens JW, Sleijfer S. ESR1 mutations: moving towards guiding treatment decision-making in metastatic breast cancer patients. Cancer Treat Rev. 2017;52:33–40. [DOI] [PubMed]

72.

Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, et al. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov. 2017;7:277–87. [DOI] [PubMed] [PMC]

73.

Reinert T, Gonçalves R, Bines J. Implications of ESR1 mutations in hormone receptor-positive breast cancer. Curr Treat Options Oncol. 2018;19:24. [DOI] [PubMed]

74.

Jeselsohn R, Bergholz JS, Pun M, Cornwell M, Liu W, Nardone A, et al. Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations. Cancer Cell. 2018;33:173–86.e5. [DOI] [PubMed] [PMC]

75.

Bahreini A, Li Z, Wang P, Levine KM, Tasdemir N, Cao L, et al. Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models. Breast Cancer Res. 2017;19:60. [DOI] [PubMed] [PMC]

76.

Harrod A, Fulton J, Nguyen VTM, Periyasamy M, Ramos-Garcia L, Lai CF, et al. Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer. Oncogene. 2017;36:2286–96. [DOI] [PubMed] [PMC]

77.

Martin LA, Ribas R, Simigdala N, Schuster E, Pancholi S, Tenev T, et al. Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance. Nat Commun. 2017;8:1865. [DOI] [PubMed] [PMC]

78.

Long X, Nephew KP. Fulvestrant (ICI 182,780)-dependent interacting proteins mediate immobilization and degradation of estrogen receptor-alpha. J Biol Chem. 2006;281:9607–15. [DOI] [PubMed]

79.

Yeh WL, Shioda K, Coser KR, Rivizzigno D, McSweeney KR, Shioda T. Fulvestrant-induced cell death and proteasomal degradation of estrogen receptor α protein in MCF-7 cells require the CSK c-Src tyrosine kinase. PLoS One. 2013;8:e60889. [DOI] [PubMed] [PMC]

80.

Deeks ED. Fulvestrant: a review in advanced breast cancer not previously treated with endocrine therapy. Drugs. 2018;78:131–7. [DOI] [PubMed]

81.

De Savi C, Bradbury RH, Rabow AA, Norman RA, de Almeida C, Andrews DM, et al. Optimization of a novel binding motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist. J Med Chem. 2015;58:8128–40. [DOI] [PubMed]

82.

Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res. 2013;19:2420–31. [DOI] [PubMed] [PMC]

83.

Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015;26:948–56. [DOI] [PubMed] [PMC]

84.

Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C, Julien J, et al. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem. 2015;58:4888–904. [DOI] [PubMed]

85.

Guo S, Zhang C, Bratton M, Mottamal M, Liu J, Ma P, et al. ZB716, a steroidal selective estrogen receptor degrader (SERD), is orally efficacious in blocking tumor growth in mouse xenograft models. Oncotarget. 2018;9:6924–37. [DOI] [PubMed] [PMC]

86.

Tria GS, Abrams T, Baird J, Burks HE, Firestone B, Gaither LA, et al. Discovery of LSZ102, a potent, orally bioavailable selective estrogen receptor degrader (SERD) for the treatment of estrogen receptor positive breast cancer. J Med Chem. 2018;61:2837–64. [DOI] [PubMed]

87.

Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;2012:CD006243. [DOI] [PubMed] [PMC]

88.

Pondé N, Brandão M, El-Hachem G, Werbrouck E, Piccart M. Treatment of advanced HER2-positive breast cancer: 2018 and beyond. Cancer Treat Rev. 2018 Jun;67:10–20. [DOI] [PubMed]

89.

Beck A, Goetsch L, Dumontet C, Corvaía N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37. [DOI] [PubMed]

90.

Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017;117:1736–42. [DOI] [PubMed] [PMC]

91.

Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91. [DOI] [PubMed] [PMC]

92.

Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419. [DOI] [PubMed]

93.

Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5:953–62. [PubMed]

94.

Xu X, De Angelis C, Burke KA, Nardone A, Hu H, Qin L, et al. HER2 reactivation through acquisition of the HER2 L755S mutation as a mechanism of acquired resistance to HER2-targeted therapy in HER2+ breast cancer. Clin Cancer Res. 2017;23:5123–34. [DOI] [PubMed] [PMC]

95.

Scaltriti M, Rojo F, Ocaña A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38. [DOI] [PubMed]

96.

Veeraraghavan J, Mistry R, Nanda S, Sethunath V, Shea M, Mitchell T, et al. Abstract 1911: HER2 L755S mutation is associated with acquired resistance to lapatinib and neratinib, and confers cross-resistance to tucatinib in HER2-positive breast cancer models. Am Assoc Cancer Res. 2020;80:1911. [DOI]

97.

Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13:4909–19. [DOI] [PubMed]

98.

Goutsouliak K, Veeraraghavan J, Sethunath V, De Angelis C, Osborne CK, Rimawi MF, et al. Towards personalized treatment for early stage HER2-positive breast cancer. Nat Rev Clin Oncol. 2020;17:233–50. [DOI] [PubMed] [PMC]

99.

Jiang Y, Deng Q, Zhao H, Xie M, Chen L, Yin F, et al. Development of stabilized peptide-based PROTACs against estrogen receptor α. ACS Chem Biol. 2018;13:628–35. [DOI] [PubMed]

100.

Li Y, Zhang S, Zhang J, Hu Z, Xiao Y, Huang J, et al. Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs). Eur J Med Chem. 2019;172:48–61. [DOI] [PubMed]

101.

Bafna D, Ban F, Rennie PS, Singh K, Cherkasov A. Computer-aided ligand discovery for estrogen receptor alpha. Int J Mol Sci. 2020;21:4193. [DOI] [PubMed] [PMC]

102.

Sakamoto KM, Kim KB, Verma R, Ransick A, Stein B, Crews CM, et al. Development of protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol Cell Proteomics. 2003;2:1350–8. [DOI] [PubMed]

103.

Rodriguez-Gonzalez A, Cyrus K, Salcius M, Kim K, Crews CM, Deshaies RJ, et al. Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer. Oncogene. 2008;27:7201–11. [DOI] [PubMed] [PMC]

104.

Kargbo RB. PROTAC-mediated degradation of estrogen receptor in the treatment of cancer. ACS Med Chem Lett. 2019;10:1367–9. [DOI] [PubMed] [PMC]

105.

Okuhira K, Demizu Y, Hattori T, Ohoka N, Shibata N, Nishimaki-Mogami T, et al. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci. 2013;104:1492–8. [DOI] [PubMed] [PMC]

106.

Ohoka N. Development of protein knockdown technology as emerging drug discovery strategy. Yakugaku Zasshi. 2018;138:1135–43. Japanese. [DOI] [PubMed]

107.

Snyder LB, Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, et al. Abstract 44: the discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer, in: experimental and molecular therapeutics. Am Assoc Cancer Res. 2021;81:44. [DOI]

108.

Arvinas and pfizer announce global collaboration to develop and commercialize PROTAC® protein degrader ARV-471 [Internet]. New York: Pfizer Inc; c2002-2021 [cited 2021 Jul 22]. Available from: https://www.pfizer.com/news/press-release/press-release-detail/arvinas-and-pfizer-announce-global-collaboration-develop?utm_source=researcher_app&utm_medium=referral&utm_campaign=RESR_MRKT_Researcher_inbound

109.

Maneiro MA, Forte N, Shchepinova MM, Kounde CS, Chudasama V, Baker JR, et al. Antibody-PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4. ACS Chem Biol. 2020;15:1306–12. [DOI] [PubMed] [PMC]

110.

Zhang X, He Y, Zhang P, Budamagunta V, Lv D, Thummuri D, et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur J Med Chem. 2020;199:112397. [DOI] [PubMed] [PMC]

111.

Noblejas-López MDM, Nieto-Jimenez C, Burgos M, Gómez-Juárez M, Montero JC, Esparís-Ogando A, et al. Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer. J Exp Clin Cancer Res. 2019;38:383. [DOI] [PubMed] [PMC]

112.

Bai L, Zhou B, Yang CY, Ji J, McEachern D, Przybranowski S, et al. Targeted degradation of BET proteins in triple-negative breast cancer. Cancer Res. 2017;77:2476–87. [DOI] [PubMed] [PMC]

113.

Cyrus K, Wehenkel M, Choi EY, Lee H, Swanson H, Kim KB. Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. ChemMedChem. 2010;5:979–85. [DOI] [PubMed] [PMC]

114.

Demizu Y, Okuhira K, Motoi H, Ohno A, Shoda T, Fukuhara K, et al. Design and synthesisofestrogenreceptor degradation inducer based on a protein knockdown strategy. Bioorg Med Chem Lett. 2012;22:1793–6. [DOI] [PubMed]

115.

Wang L, Guillen VS, Sharma N, Flessa K, Min J, Carlson KE, et al. New class of selective estrogen receptor degraders (SERDs): expanding the toolbox of PROTAC degrons. ACS Med Chem Lett. 2018;9:803–8. [DOI] [PubMed] [PMC]

116.

Tecalco-Cruz AC, Ramírez-Jarquín JO, Cruz-Ramos E. Estrogen receptor alpha and its ubiquitination in breast cancer cells. Curr Drug Targets. 2019;20:690–704. [DOI] [PubMed]