Mechanisms of endocrine resistance [3]
| Resistance pathway | Mechanism | Reference(s) |
|---|---|---|
| ER expression and activity loss | Mutations | [32] |
| Gene regulation | [33] | |
| Post-transcriptional modifications (e.g., splice variants, mRNA stability) | [34, 35] | |
| Post-translational modifications | [36] | |
| Transcriptional machinery of ER | Down-regulation of co-repressors (e.g., NCoR) | [37] |
| Over-expression of co-activators (e.g., AIB1) | [38, 39] | |
| Increased expression of transcriptional factors (e.g., AP-1, SP-1, NFκB) | [40, 41] | |
| Cross-talk between ER and RTKs | EGF/EGFR | [42–44] |
| HER2 | [44–46] | |
| IGF1R | [47, 48] | |
| PI3Ks/Akt | [48–52] | |
| p44/42 MAPK | [53, 54] | |
| Stress-induced kinases (JNK, p38 MAPK) | [55] | |
| Cell cycle regulators | Over-expression of positive regulators (e.g., MYC and cyclins E1 and D1) | [56] |
| Reduced expression of negative regulators (e.g., p21 and p27) | [57, 58] | |
| Over-expression of anti-apoptotic molecules (e.g., BCL-XL) | [59] | |
| Reduced expression of pro-apoptotic molecules (e.g., BCL-2-interacting killer and caspase 9) | [59] |
AIB1: amplified in breast 1; Akt: protein kinase B; AP-1: activator protein 1; BCL-2: B-cell lymphoma 2; BCL-XL: B-cell lymphoma-extra large; EGF: epidermal growth factor; EGFR: EGF receptor; IGF1R: insulin growth factor 1 receptor; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; NCoR: nuclear receptor corepressor; PI3Ks: phosphatidylinositol 3-kinases; SP-1: specificity protein 1
Note. Reprinted from “Biological mechanisms and clinical implications of endocrine resistance in breast cancer,” by Giuliano M, Schifp R, Osborne CK, Trivedi MV. Breast. 2011;20 Suppl 3:S42–9 (https://linkinghub.elsevier.com/retrieve/pii/S0960977611702934). CC BY-NC-ND.