Table Info

Table 2.

Summary of clinical trials leading to the approval of new drugs to overcome endocrine resistance in HR⁺/HER2^– BC

Drug	Target	Study	Phase	Population	Therapy line	Treatment arms	Outcome	Reference(s)
CDK4/6i
Palbociclib	CDK4/6	PALOMA-3 NCT01942135	III	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Palbociclib + FULV vs. placebo + FULV	mPFS: 11.2 mo vs. 4.6 mo; hazard ratio: 0.46; P < 0.0001 mOS: 34.9 mo vs. 28 mo; hazard ratio: 0.81; P = 0.09	[72, 74]
Ribociclib	CDK4/6	MONALEESA-3 NCT02422615	III	HR⁺/HER2^– postmenopausal advanced BC	First or second line	Ribociclib + FULV vs. placebo + FULV	mPFS: 21.0 mo vs. 13 mo; hazard ratio: 0.59; P < 0.001 mOS: 54 mo vs. 42 mo; hazard ratio: 0.73; P < 0.01	[75, 76]
Abemaciclib	CDK4/6	MONARCH 2 NCT02107703	III	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Abemaciclib + FULV vs. placebo + FULV	mPFS: 16.4 mo vs. 9.3 mo; hazard ratio: 0.55; P < 0.001 mOS: 46.7 mo vs. 37.3 mo; hazard ratio: 0.75; P = 0.01	[73, 77]
Palbociclib	CDK4/6	PALOMA-2 NCT01740427	III	HR⁺/HER2^– postmenopausal advanced BC	First line	Palbociclib + letrozole vs. placebo + letrozole	mPFS: 27.6 mo vs. 14.5 mo; hazard ratio 0.56, P < 0.001 ORR: 42% vs. 35%	[69, 78]
Ribociclib	CDK4/6	MONALEESA-2 NCT01958021	III	HR⁺/HER2^– postmenopausal advanced BC	First line	Ribociclib + letrozole vs. placebo + letrozole	mPFS: 25.3 mo vs. 16 mo; hazard ratio: 0.57; P < 0.001 ORR: 43% vs. 29%	[79]
Ribociclib	CDK4/6	MONALEESA-7 NCT02278120	III	HR⁺/HER2^– premenopausal advanced BC	First line	Ribociclib + letrozole/anastrozole/TAM + goserelin vs. placebo + letrozole/anastrozole/TAM + goserelin	mPFS: 24 mo vs. 13 mo; hazard ratio: 0.55, P < 0.0001 mOS: n.r. vs. 40.7 mo; hazard ratio: 0.71; P = 0.00973	[70, 80]
Abemaciclib	CDK4/6	MONARCH 3 NCT02246621	III	HR⁺/HER2^– postmenopausal advanced BC	First line	Abemaciclib + letrozole vs. placebo + letrozole	mPFS: 28.2 mo vs. 14.2 mo; hazard ratio: 0.54; P < 0.001 ORR: 59% vs. 44%	[81]
PI3K/AKT/mTOR inhibitors
Everolimus	mTOR1	BOLERO-2 NCT00863655	III	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Everolimus + exemestane vs. placebo + exemestane	mPFS: 10.6 mo vs. 4.1 mo; hazard ratio: 0.36, P < 0.001 ORR: 7% vs. 0.4%	[82]
		MANTA NCT02216786	II	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Everolimus + FULV vs. placebo + FULV	mPFS: 12.3 mo vs. 5.4 mo; hazard ratio: 0.63, P = 0.01	[83]
		PrE0102 NCT01797120	II	HR⁺/HER2^– postmenopausal advanced BC	Second or later lines	Everolimus + FULV vs. placebo + FULV	mPFS: 10.3 mo vs. 5.1 mo; hazard ratio: 0.61, P = 0.02	[84]
Alpelisib	Class I PI3K p110α	SOLAR-1 NCT02437318	III	HR⁺/HER2^– postmenopausal advanced BC	First or second line	Alpelisib + FULV vs. placebo + FULV	mPFS: 11.0 mo vs. 5.7 mo; hazard ratio: 0.65, P < 0.001 ORR: 26.6% vs. 12.8%; PIK3CA- mutant subset mOS: 39.3 mo vs. 31.4 mo; hazard ratio: 0.86, P = 0.15	[71, 85]

mo: months; mOS: median overall survival; mPFS: median PFS; mTOR: mammalian target of rapamycin; n.r.: not reached; ORR: overall response rate; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

Declarations

Acknowledgments

The authors acknowledge Joana Cavaco Silva for assisting in manuscript revision.

Author contributions

ISP: contributed to the manuscript design and literature analysis, wrote part of the introduction and the NFκB pathway as well as global revision to the article.

CA: contributed to the initial design of the article, wrote Notch pathway and a substantial contribution and regulators of cell cycle apoptosis, as well as to global manuscript revision.

IG: contributed to the manuscript design and literature analysis, wrote part of the introduction and created some figures.

SC: wrote the RANK-RANKL pathway chapter, and full manuscript revision.

TRP: made the revision of TKRs and alternative pathways, made Table 2 and Figures 3 and 4; also contributed to global manuscript revision.

RTS: specially contributed for the initial design of the article, contributed to the conclusion and review the final manuscript.

LC: contributed to conceptualization, design, direction and overall supervision of the manuscript.

All the authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

IG is supported by the FCT PhD grant SFRH/BD/139178/2018. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. [DOI] [PubMed]

Harbeck N, Gnant M. Breast cancer. Lancet. 2017;389:1134–50. [DOI] [PubMed]

Giuliano M, Schifp R, Osborne CK, Trivedi MV. Biological mechanisms and clinical implications of endocrine resistance in breast cancer. Breast. 2011;20 Suppl 3:S42–9. [DOI] [PubMed]

Rani A, Stebbing J, Giamas G, Murphy J. Endocrine resistance in hormone receptor positive breast cancer—from mechanism to therapy. Front Endocrinol (Lausanne). 2019;10:245. [DOI] [PubMed] [PMC]

Haque MM, Desai KV. Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol (Lausanne). 2019;10:573. [DOI] [PubMed] [PMC]

Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9:631–43. [DOI] [PubMed]

Guillette TC, Jackson TW, Belcher SM. Duality of estrogen receptor β action in cancer progression. Curr Opin Pharmacol. 2018;41:66–73. [DOI] [PubMed] [PMC]

Speirs V, Parkes AT, Kerin MJ, Walton DS, Carleton PJ, Fox JN, et al. Coexpression of estrogen receptor alpha and beta: poor prognostic factors in human breast cancer? Cancer Res. 1999;59:525–8. [PubMed]

Speirs V, Malone C, Walton DS, Kerin MJ, Atkin SL. Increased expression of estrogen receptor beta mRNA in tamoxifen-resistant breast cancer patients. Cancer Res. 1999;59:5421–4. [PubMed]

10.

Guo L, Zhang Y, Zhang W, Yilamu D. Correlation between estrogen receptor β expression and the curative effect of endocrine therapy in breast cancer patients. Exp Ther Med. 2014;7:1568–72. [DOI] [PubMed] [PMC]

11.

Guo L, Zhang YU, Yilamu D, Liu S, Guo C. ERβ overexpression results in endocrine therapy resistance and poor prognosis in postmenopausal ERα-positive breast cancer patients. Oncol Lett. 2016;11:1531–6. [DOI] [PubMed] [PMC]

12.

Belachew EB, Sewasew DT. Molecular mechanisms of endocrine resistance in estrogen-positive breast cancer. Front Endocrinol (Lausanne). 2021;12:599586. Erratum in: Front Endocrinol (Lausanne). 2021;12:689705. [DOI] [PubMed] [PMC]

13.

Naik N, Madani A, Esteva A, Keskar NS, Press MF, Ruderman D, et al. Deep learning-enabled breast cancer hormonal receptor status determination from base-level H&E stains. Nat Commun. 2020;11:5727. [DOI] [PubMed] [PMC]

14.

Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2:101–12. [DOI] [PubMed]

15.

Zattarin E, Leporati R, Ligorio F, Lobefaro R, Vingiani A, Pruneri G, et al. Hormone receptor loss in breast cancer: molecular mechanisms, clinical settings, and therapeutic implications. Cells. 2020;9:2644. [DOI] [PubMed] [PMC]

16.

Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol. 2003;21:1973–9. [DOI] [PubMed]

17.

Ueno T, Saji S, Chiba T, Kamma H, Isaka H, Itoh H, et al. Progesterone receptor expression in proliferating cancer cells of hormone-receptor-positive breast cancer. Tumour Biol. 2018;40:1010428318811025. [DOI] [PubMed]

18.

Kunc M, Popęda M, Biernat W, Senkus E. Lost but not least—novel insights into progesterone receptor loss in estrogen receptor-positive breast cancer. Cancers (Basel). 2021;13:4755. [DOI] [PubMed] [PMC]

19.

Ma CX, Sanchez CG, Ellis MJ. Predicting endocrine therapy responsiveness in breast cancer. Oncology (Williston Park). 2009;23:133–42. [PubMed]

20.

Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 2004;11:643–58. [DOI] [PubMed]

21.

Hoskins JM, Carey LA, McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer. 2009;9:576–86. [DOI] [PubMed]

22.

Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH. Pathways to tamoxifen resistance. Cancer Lett. 2007;256:1–24. [DOI] [PubMed] [PMC]

23.

Luque-Bolivar A, Pérez-Mora E, Villegas VE, Rondón-Lagos M. Resistance and overcoming resistance in breast cancer. Breast Cancer (Dove Med Press). 2020;12:211–29. [DOI] [PubMed] [PMC]

24.

Mills JN, Rutkovsky AC, Giordano A. Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors. Curr Opin Pharmacol. 2018;41:59–65. [DOI] [PubMed] [PMC]

25.

Clarke R, Shajahan AN, Riggins RB, Cho Y, Crawford A, Xuan J, et al. Gene network signaling in hormone responsiveness modifies apoptosis and autophagy in breast cancer cells. J Steroid Biochem Mol Biol. 2009;114:8–20. [DOI] [PubMed] [PMC]

26.

Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol. 2014;5:248–62. [DOI] [PubMed] [PMC]

27.

Liu CY, Wu CY, Petrossian K, Huang TT, Tseng LM, Chen S. Treatment for the endocrine resistant breast cancer: current options and future perspectives. J Steroid Biochem Mol Biol. 2017;172:166–75. [DOI] [PubMed]

28.

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

29.

Masuda N, Nishimura R, Takahashi M, Inoue K, Ohno S, Iwata H, et al. Palbociclib in combination with letrozole as first-line treatment for advanced breast cancer: a Japanese phase II study. Cancer Sci. 2018;109:803–13. [DOI] [PubMed] [PMC]

30.

Lv Q, Guan S, Zhu M, Huang H, Wu J, Dai X. FGFR1 is associated with tamoxifen resistance and poor prognosis of ER-positive breast cancers by suppressing ER protein expression. Technol Cancer Res Treat. 2021;20:15330338211004935. [DOI] [PubMed] [PMC]

31.

Dong C, Wu J, Chen Y, Nie J, Chen C. Activation of PI3K/AKT/mTOR pathway causes drug resistance in breast cancer. Front Pharmacol. 2021;12:628690. [DOI] [PubMed] [PMC]

32.

Herynk MH, Fuqua SA. Estrogen receptor mutations in human disease. Endocr Rev 2004;25:869–98. [DOI] [PubMed]

33.

Iwase H, Greenman JM, Barnes DM, Bobrow L, Hodgson S, Mathew CG. Loss of heterozygosity of the oestrogen receptor gene in breast cancer. Br J Cancer. 1995;71:448–50. [DOI] [PubMed] [PMC]

34.

Adams BD, Furneaux H, White BA. The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-α (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines. Mol Endocrinol 2007;21:1132–47. [DOI] [PubMed]

35.

Shi L, Dong B, Li Z, Lu Y, Ouyang T, Li J, et al. Expression of ER-α36, a novel variant of estrogen receptor α, and resistance to tamoxifen treatment in breast cancer. J Clin Oncol. 2009;27:3423–9. DOI: [DOI] [PubMed] [PMC]

36.

Gururaj AE, Rayala SK, Vadlamudi RK, Kumar R. Novel mechanisms of resistance to endocrine therapy: genomic and nongenomic considerations. Clin Cancer Res. 2006;12:1001s–7s. [DOI] [PubMed]

37.

Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TM, Schiff R, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci U S A. 1998;95:2920–5. [DOI] [PubMed] [PMC]

38.

Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–35. [DOI] [PubMed]

39.

Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst. 2003;95:353–61. [DOI] [PubMed]

40.

Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, et al. Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer. 2007;7:59. [DOI] [PubMed] [PMC]

41.

Schiff R, Reddy P, Ahotupa M, Coronado-Heinsohn E, Grim M, Hilsenbeck SG, et al. Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst. 2000;92:1926–34. [DOI] [PubMed]

42.

Lupien M, Meyer CA, Bailey ST, Eeckhoute J, Cook J, Westerling T, et al. Growth factor stimulation induces a distinct ERα cistrome underlying breast cancer endocrine resistance. Genes Dev. 2010;24:2219–27. [DOI] [PubMed] [PMC]

43.

Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 2008;68:826–33. [DOI] [PubMed]

44.

Arpino G, Green SJ, Allred DC, Lew D, Martino S, Osborne CK, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a southwest oncology group study. Clin Cancer Res. 2004;10:5670–6. [DOI] [PubMed]

45.

Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95:142–53. [DOI] [PubMed]

46.

De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005;11:4741–8. [DOI] [PubMed]

47.

Miller TW, Pérez-Torres M, Narasanna A, Guix M, Stål O, Pérez-Tenorio G, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69:4192–201. [DOI] [PubMed] [PMC]

48.

Cui X, Zhang P, Deng W, Oesterreich S, Lu Y, Mills GB, et al. Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer. Mol Endocrinol. 2003;17:575–88. [DOI] [PubMed]

49.

Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α: a new model for anti-estrogen resistance. J Biol Chem. 2001;276:9817–24. [DOI] [PubMed]

50.

DeGraffenried LA, Friedrichs WE, Fulcher L, Fernandes G, Silva JM, Peralba JM, et al. Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity. Ann Oncol. 2003;14:1051–6. [DOI] [PubMed]

51.

deGraffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res. 2004;10:8059–67. [DOI] [PubMed]

52.

Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER⁺ breast cancer. Breast Cancer Res. 2010;12:R40. [DOI] [PubMed] [PMC]

53.

Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995;270:1491–4. [DOI] [PubMed]

54.

Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996;15:2174–83. [DOI] [PubMed] [PMC]

55.

Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol. 2005;23:2469–76. [DOI] [PubMed]

56.

Butt AJ, McNeil CM, Musgrove EA, Sutherland RL. Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer. 2005;12 Suppl 1:S47–59. [DOI] [PubMed]

57.

Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8:253–67. [DOI] [PubMed]

58.

Pérez-Tenorio G, Berglund F, Merca AE, Nordenskjöld B, Rutqvist LE, Skoog L, et al. Cytoplasmic p21WAF1/CIP1 correlates with Akt activation and poor response to tamoxifen in breast cancer. Int J Oncol. 2006;28:1031–42. [DOI] [PubMed]

59.

Kumar R, Mandal M, Lipton A, Harvey H, Thompson CB. Overexpression of HER2 modulates bcl-2, bcl-XL, and tamoxifen-induced apoptosis in human MCF-7 breast cancer cells. Clin Cancer Res. 1996;2:1215–9. [PubMed]

60.

Hartkopf AD, Grischke EM, Brucker SY. Endocrine-resistant breast cancer: mechanisms and treatment. Breast Care. 2020;15:347–54. [DOI] [PubMed] [PMC]

61.

Clarke R, Tyson JJ, Dixon JM. Endocrine resistance in breast cancer—an overview and update. Mol Cell Endocrinol. 2015;418:220–34. [DOI] [PubMed] [PMC]

62.

Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244–9. [PubMed]

63.

Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020;37:496–513. [DOI] [PubMed] [PMC]

64.

Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12:573–83. [DOI] [PubMed] [PMC]

65.

Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Structural underpinnings of estrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer. 2018;18:377–88. Erratum in: Nat Rev Cancer. 2018;18:662. [DOI] [PubMed] [PMC]

66.

Hua H, Zhang H, Kong Q, Jiang Y. Mechanisms for estrogen receptor expression in human cancer. Exp Hematol Oncol. 2018;7:24. [DOI] [PubMed] [PMC]

67.

Nair BC, Vadlamudi RK. Regulation of hormonal therapy resistance by cell cycle machinery. Gene Ther Mol Biol. 2008;12:395. [PubMed] [PMC]

68.

Lange CA, Yee D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr Relat Cancer. 2011;18:C19–24. [DOI] [PubMed] [PMC]

69.

Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375:1925–36. [DOI] [PubMed]

70.

Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19:904–15. [DOI] [PubMed]

71.

André F, Ciruelos EM, Juric D, Loibl S, Campone M, Mayer IA, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32:208–17. [DOI] [PubMed]

72.

Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926–36. [DOI] [PubMed]

73.

Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR⁺/HER2^– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875–84. [DOI] [PubMed]

74.

Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:425–39. Erratum in: Lancet Oncol. 2016;17:e136. Erratum in: Lancet Oncol. 2016;17:e270. [DOI] [PubMed]

75.

Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36:2465–72. [DOI] [PubMed]

76.

Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382:514–24. [DOI] [PubMed]

77.

Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 2020;6:116–24. [DOI] [PubMed] [PMC]

78.

Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019;174:719–29. [DOI] [PubMed] [PMC]

79.

Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29:1541–7. Erratum in: Ann Oncol. 2019;30:1842. [DOI] [PubMed]

80.

Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381:307–16. [DOI] [PubMed]

81.

Johnston S, O’Shaughnessy J, Martin M, Huober J, Toi M, Sohn J, et al. Abemaciclib as initial therapy for advanced breast cancer: MONARCH 3 updated results in prognostic subgroups. NPJ Breast Cancer. 2021;7:80. [DOI] [PubMed] [PMC]

82.

Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9. [DOI] [PubMed] [PMC]

83.

Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S, et al. Fulvestrant plus vistusertib vs fulvestrant plus everolimus vs fulvestrant alone for women with hormone receptor-positive metastatic breast cancer: the MANTA phase 2 randomized clinical trial. JAMA Oncol. 2019;5:1556–64. Erratum in: JAMA Oncol. 2021;7:312. [DOI] [PubMed] [PMC]

84.

Kornblum N, Zhao F, Manola J, Klein P, Ramaswamy B, Brufsky A, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36:1556–63. [DOI] [PubMed] [PMC]

85.

André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al.; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380:1929–40. [DOI] [PubMed]

86.

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28:4594–600. Erratum in: J Clin Oncol. 2011;29:2293. [DOI] [PubMed]

87.

Chow LWC, Lie EF, Toi M. Advances in EGFR/HER2-directed clinical research on breast cancer. Adv Cancer Res. 2020;147:375–428. [DOI] [PubMed]

88.

Croessmann S, Formisano L, Kinch LN, Gonzalez-Ericsson PI, Sudhan DR, Nagy RJ, et al. Combined blockade of activating ERBB2 mutations and ER results in synthetic lethality of ER⁺/HER2 mutant breast cancer. Clin Cancer Res. 2019;25:277–89. [DOI] [PubMed] [PMC]

89.

Nayar U, Cohen O, Kapstad C, Cuoco MS, Waks AG, Wander SA, et al. Acquired HER2 mutations in ER⁺ metastatic breast cancer confer resistance to estrogen receptor-directed therapies. Nat Genet. 2019;51:207–16. [DOI] [PubMed]

90.

Razavi P, Chang MT, Xu G, Bandlamudi C, Ross DS, Vasan N, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34:427–38.e6. [DOI] [PubMed] [PMC]

91.

Smyth LM, Piha-Paul SA, Won HH, Schram AM, Saura C, Loi S, et al. Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer. Cancer Discov. 2020;10:198–213. [DOI] [PubMed] [PMC]

92.

Perez-Garcia J, Muñoz-Couselo E, Soberino J, Racca F, Cortes J. Targeting FGFR pathway in breast cancer. Breast. 2018;37:126–33. [DOI] [PubMed]

93.

Giltnane JM, Hutchinson KE, Stricker TP, Formisano L, Young CD, Estrada MV, et al. Genomic profiling of ER⁺ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance. Sci Transl Med. 2017;9:eaai7993. Erratum in: Sci Transl Med. 2019;11:eaaw7620. [DOI] [PubMed] [PMC]

94.

Chew NJ, Lim Kam Sian TCC, Nguyen EV, Shin SY, Yang J, Hui MN, et al. Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models. Breast Cancer Res. 2021;23:82. [DOI] [PubMed] [PMC]

95.

Turczyk L, Kitowska K, Mieszkowska M, Mieczkowski K, Czaplinska D, Piasecka D, et al. FGFR2-driven signaling counteracts tamoxifen effect on ERα-positive breast cancer cells. Neoplasia. 2017;19:791–804. [DOI] [PubMed] [PMC]

96.

Levine KM, Priedigkeit N, Basudan A, Tasdemir N, Sikora MJ, Sokol ES, et al. FGFR4 overexpression and hotspot mutations in metastatic ER⁺ breast cancer are enriched in the lobular subtype. NPJ Breast Cancer. 2019;5:19. [DOI] [PubMed] [PMC]

97.

Garcia-Recio S, Thennavan A, East MP, Parker JS, Cejalvo JM, Garay JP, et al. FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease. J Clin Invest. 2020;130:4871–87. [DOI] [PubMed] [PMC]

98.

Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–32. [DOI] [PubMed]

99.

Miller TW, Hennessy BT, González-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120:2406–13. [DOI] [PubMed] [PMC]

100.

Vitale SR, Martorana F, Stella S, Motta G, Inzerilli N, Massimino M, et al. PI3K inhibition in breast cancer: identifying and overcoming different flavors of resistance. Crit Rev Oncol Hematol. 2021;162:103334. [DOI] [PubMed]

101.

Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020;21:345–57. [DOI] [PubMed] [PMC]

102.

Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35:2251–9. Erratum in: J Clin Oncol. 2019;37:360. [DOI] [PubMed] [PMC]

103.

Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, et al. Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1^E17K-mutant, ER-positive metastatic breast cancer. Clin Cancer Res. 2020;26:3947–57. [DOI] [PubMed] [PMC]

104.

Alves CL, Ehmsen S, Terp MG, Portman N, Tuttolomondo M, Gammelgaard OL, et al. Co-targeting CDK4/6 and AKT with endocrine therapy prevents progression in CDK4/6 inhibitor and endocrine therapy-resistant breast cancer. Nat Commun. 2021;12:5112. Erratum in: Nat Commun. 2021;12:5588. [DOI] [PubMed] [PMC]

105.

Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol. 2016;34:419–26. Erratum in: J Clin Oncol. 2019;37:354. Erratum in: J Clin Oncol. 2019;37:355. [DOI] [PubMed] [PMC]

106.

Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is essential for osteoclast and lymph node development. 1999;13:2412–24. [DOI] [PubMed] [PMC]

107.

Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K, et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998;253:395–400. [DOI] [PubMed]

108.

Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11:401–19. [DOI] [PubMed]

109.

Lipton A, Goessl C. Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis. Bone. 2011;48:96–9. [DOI] [PubMed]

110.

Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008;68:92–104. [DOI] [PubMed]

111.

Casimiro S, Mohammad KS, Pires R, Tato-Costa J, Alho I, Teixeira R, et al. RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro. PLoS One. 2013;8:e63153. [DOI] [PubMed] [PMC]

112.

Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440:692–6. [DOI] [PubMed]

113.

Mori K, Le Goff B, Charrier C, Battaglia S, Heymann D, Rédini F. DU145 human prostate cancer cells express functional receptor activator of NFkappaB: new insights in the prostate cancer bone metastasis process. Bone. 2007;40:981–90. [DOI] [PubMed]

114.

Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye JF, et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med. 2013;5:182ra55. [DOI] [PubMed]

115.

Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468:103–7. [DOI] [PubMed]

116.

Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468:98–102. [DOI] [PubMed] [PMC]

117.

Casimiro S, Vilhais G, Gomes I, Costa L. The roadmap of RANKL/RANK pathway in cancer. Cells. 2021;10:1978. [DOI] [PubMed] [PMC]

118.

Pfitzner BM, Branstetter D, Loibl S, Denkert C, Lederer B, Schmitt WD, et al. RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res Treat. 2014;145:307–15. [DOI] [PubMed]

119.

Santini D, Perrone G, Roato I, Godio L, Pantano F, Grasso D, et al. Expression pattern of receptor activator of NFκB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol. 2011;226:780–4. [DOI] [PubMed]

120.

Santini D, Schiavon G, Vincenzi B, Gaeta L, Pantano F, Russo A, et al. Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS One. 2011;6:e19234. [DOI] [PubMed] [PMC]

121.

Zhang L, Teng Y, Zhang Y, Liu J, Xu L, Qu J, et al. Receptor activator for nuclear factor κ B expression predicts poor prognosis in breast cancer patients with bone metastasis but not in patients with visceral metastasis. J Clin Pathol. 2012;65:36–40. [DOI] [PubMed]

122.

Owen S, Ye L, Sanders AJ, Mason MD, Jiang WG. Expression profile of receptor activator of nuclear-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) in breast cancer. Anticancer Res. 2013;33:199–206. [PubMed]

123.

Park HS, Lee A, Chae BJ, Bae JS, Song BJ, Jung SS. Expression of receptor activator of nuclear factor kappa-B as a poor prognostic marker in breast cancer. J Surg Oncol. 2014;110:807–12. [DOI] [PubMed]

124.

Gomes I, de Almeida BP, Dâmaso S, Mansinho A, Correia I, Henriques S, et al. Expression of receptor activator of NFkB (RANK) drives stemness and resistance to therapy in ER⁺HER2^– breast cancer. Oncotarget. 2020;11:1714–28. [DOI] [PubMed] [PMC]

125.

Benítez S, Cordero A, Santamaría PG, Redondo-Pedraza J, Rocha AS, Collado-Solé A, et al. RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness. Dev Cell. 2021;56:1727–41.e7. [DOI] [PubMed] [PMC]

126.

Pellegrini P, Cordero A, Gallego MI, Dougall WC, Muñoz P, Pujana MA, et al. Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis. Stem Cells. 2013;31:1954–65. Erratum in: Stem Cells. 2014;32:1057. Erratum in: Stem Cells. 2014;32:600. [DOI] [PubMed]

127.

International Prognostic Factors Study Group; Lorch A, Beyer J, Bascoul-Mollevi C, Kramar A, Einhorn LH, Necchi A, et al. Prognostic factors in patients with metastatic germ cell tumors who experienced treatment failure with cisplatin-based first-line chemotherapy. J Clin Oncol. 2010;28:4906–11. [DOI] [PubMed]

128.

Yoldi G, Pellegrini P, Trinidad EM, Cordero A, Gomez-Miragaya J, Serra-Musach J, et al. RANK signaling blockade reduces breast cancer recurrence by inducing tumor cell differentiation. Cancer Res. 2016;76:5857–69. [DOI] [PubMed]

129.

Cao Y, Bonizzi G, Seagroves TN, Greten FR, Johnson R, Schmidt EV, et al. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell. 2001;107:763–75. [DOI] [PubMed]

130.

Sun SC. The noncanonical NF-κB pathway. Immunol Rev. 2012;246:125–40. [DOI] [PubMed] [PMC]

131.

Sanz-Moreno A, Palomeras S, Pedersen K, Morancho B, Pascual T, Galván P, et al. RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer. Breast Cancer Res. 2021;23:42. [DOI] [PubMed] [PMC]

132.

Tsubaki M, Komai M, Fujimoto SI, Itoh T, Imano M, Sakamoto K, et al. Activation of NF-κB by the RANKL/RANK system up-regulates snail and twist expressions and induces epithelial-to-mesenchymal transition in mammary tumor cell lines. J Exp Clin Cancer Res. 2013;32:62. [DOI] [PubMed] [PMC]

133.

Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–66. [DOI] [PubMed]

134.

Zhou Y, Eppenberger-Castori S, Eppenberger U, Benz CC. The NFkappaB pathway and endocrine-resistant breast cancer. Endocr Relat Cancer. 2005;12 Suppl 1:S37–46. [DOI] [PubMed]

135.

Rhodes LV, Bratton MR, Zhu Y, Tilghman SL, Muir SE, Salvo VA, et al. Effects of SDF-1-CXCR4 signaling on microRNA expression and tumorigenesis in estrogen receptor-alpha (ER-α)-positive breast cancer cells. Exp Cell Res. 2011;317:2573–81. [DOI] [PubMed] [PMC]

136.

van Agthoven T, Veldscholte J, Smid M, van Agthoven TLA, Vreede L, Broertjes M, et al. Functional identification of genes causing estrogen independence of human breast cancer cells. Breast Cancer Res Treat. 2009;114:23–30. [DOI] [PubMed]

137.

Cao Y, Karin M. NF-kappaB in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2003;8:215–23. [DOI] [PubMed]

138.

Perkins ND. The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer. 2012;12:121–32. [DOI] [PubMed]

139.

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. Erratum in: Cancer Res. 2010;70:854. Erratum in: Cancer Res. 2010;70:2140. [DOI] [PubMed] [PMC]

140.

Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997;17:3629–39. [DOI] [PubMed] [PMC]

141.

Nakshatri N, Goulet RJ Jr. NF-kappaB and breast cancer. Curr Probl Cancer. 2002;26:282–309. [DOI] [PubMed]

142.

Wang CY, Guttridge DC, Mayo MW, Baldwin AS Jr. NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol. 1999;19:5923–9. [DOI] [PubMed] [PMC]

143.

Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell. 2017;168:37–57. [DOI] [PubMed] [PMC]

144.

Sas L, Lardon F, Vermeulen PB, Hauspy J, Van Dam P, Pauwels P, et al. The interaction between ER and NFκB in resistance to endocrine therapy. Breast Cancer Res. 2012;14:212. [DOI] [PubMed] [PMC]

145.

Khongthong P, Roseweir AK, Edwards J. The NF-KB pathway and endocrine therapy resistance in breast cancer. Endocr Relat Cancer. 2019;26:R369–80. [DOI] [PubMed]

146.

Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621–63. [DOI] [PubMed]

147.

Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12:86. [DOI] [PubMed] [PMC]

148.

Wang X, Fang Y, Sun W, Xu Z, Zhang Y, Wei X, et al. Endocrinotherapy resistance of prostate and breast cancer: importance of the NF-κB pathway (review). Int J Oncol. 2020;56:1064–74. [DOI] [PubMed]

149.

Pasparakis M, Luedde T, Schmidt-Supprian M. Dissection of the NF-kappaB signalling cascade in transgenic and knockout mice. Cell Death Differ. 2006;13:861–72. [DOI] [PubMed]

150.

Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene. 2006;25:6758–80. [DOI] [PubMed]

151.

Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17:545–58. [DOI] [PubMed] [PMC]

152.

Maubach G, Feige MH, Lim MCC, Naumann M. NF-kappaB-inducing kinase in cancer. Biochim Biophys Acta Rev Cancer. 2019;1871:40–9. [DOI] [PubMed]

153.

Gray CM, Remouchamps C, McCorkell KA, Solt LA, Dejardin E, Orange JS, et al. Noncanonical NF-κB signaling is limited by classical NF-κB activity. Sci Signal. 2014;7:ra13. [DOI] [PubMed] [PMC]

154.

Yde CW, Emdal KB, Guerra B, Lykkesfeldt AE. NFκB signaling is important for growth of antiestrogen resistant breast cancer cells. Breast Cancer Res Treat. 2012;135:67–78. [DOI] [PubMed]

155.

Rwigemera A, Mamelona J, Martin LJ. Inhibitory effects of fucoxanthinol on the viability of human breast cancer cell lines MCF-7 and MDA-MB-231 are correlated with modulation of the NF-kappaB pathway. Cell Biol Toxicol. 2014;30:157–67. [DOI] [PubMed]

156.

Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278:21631–8. [DOI] [PubMed]

157.

Pratt MAC, Bishop TE, White D, Yasvinski G, Ménard M, Niu MY, et al. Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence. Mol Cell Biol. 2003;23:6887–900. [DOI] [PubMed] [PMC]

158.

Fan W, Chang J, Fu P. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Future Med Chem. 2015;7:1511–9. [DOI] [PubMed] [PMC]

159.

Jiang X, Shapiro DJ. The immune system and inflammation in breast cancer. Mol Cell Endocrinol. 2014;382:673–82. [DOI] [PubMed] [PMC]

160.

Jiang X. Harnessing the immune system for the treatment of breast cancer. J Zhejiang Univ Sci B. 2014;15:1–15. [DOI] [PubMed] [PMC]

161.

Oida K, Matsuda A, Jung K, Xia Y, Jang H, Amagai Y, et al. Nuclear factor-κB plays a critical role in both intrinsic and acquired resistance against endocrine therapy in human breast cancer cells. Sci Rep. 2014;4:4057. [DOI] [PubMed] [PMC]

162.

Nehra R, Riggins RB, Shajahan AN, Zwart A, Crawford AC, Clarke R. BCL2 and CASP8 regulation by NF-kappaB differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and -resistant breast cancer cells. FASEB J. 2010;24:2040–55. [DOI] [PubMed] [PMC]

163.

Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin AS Jr. Selective activation of NF-kappa B subunits in human breast cancer: potential roles for NF-kappa B2/p52 and for Bcl-3. Oncogene. 2000;19:1123–31. [DOI] [PubMed]

164.

Prescott JA, Cook SJ. Targeting IKKβ in cancer: challenges and opportunities for the therapeutic utilisation of IKKβ inhibitors. Cells. 2018;7:115. [DOI] [PubMed] [PMC]

165.

Mollen EWJ, Ient J, Tjan-Heijnen VCG, Boersma LJ, Miele L, Smidt ML, et al. Moving breast cancer therapy up a notch. Front Oncol. 2018;8:518. [DOI] [PubMed] [PMC]

166.

Nandi A, Chakrabarti R. The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance. Genes Dev. 2020;34:1422–38. [DOI] [PubMed] [PMC]

167.

BeLow M, Osipo C. Notch signaling in breast cancer: a role in drug resistance. Cells. 2020;9:2204. [DOI] [PubMed] [PMC]

168.

Meisel CT, Porcheri C, Mitsiadis TA. Cancer stem cells, quo vadis? The Notch signaling pathway in tumor initiation and progression. Cells. 2020;9:1879. [DOI] [PubMed] [PMC]

169.

Moore G, Annett S, McClements L, Robson T. Top Notch targeting strategies in cancer: a detailed overview of recent insights and current perspectives. Cells. 2020;9:1503. [DOI] [PubMed] [PMC]