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Deciphering antihormone-induced compensatory mechanisms in breast cancer and their therapeutic implications
J M W Gee1, V E Shaw, S E Hiscox
1Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff, Wales, UK. gee@cardiff.ac.uk
Abstract:
Breast cancer inhibition by antihormones is rarely complete, and our studies using responsive models reveal the remarkable flexibility of breast cancer cells in recruiting alternative signalling to limit maximal anti-tumour effects of oestrogen receptor alpha (ER) blockade. The recruited mechanism involves antihormone-induced expression of oestrogen-repressed signalling genes. For example, epidermal growth factor receptor gene (EGFR) is induced by antioestrogens and maintains residual kinase and ER phosphorylation, cell survival genes, and thereby allows incomplete antihormone response and emergence of resistance. Microarrays are revealing the breadth of antihormone-induced genes that may attenuate growth inhibition, including NFkappaB, Bag1, 14-3-3zeta and tyrosine kinases, such as HER2 and Lyn. Three concepts are emerging: first, some genes are induced exclusively by antioestrogens, while others extend to oestrogen deprivation; secondly, some are transiently induced, while others persist into resistance; finally, some confer additional adverse features when tumour cells are in an appropriate context. Among the latter is CD59 whose antioestrogen induction may permit evasion of immune surveillance in vivo. Also, induction of pro-invasive genes (including NFkappaB, RhoE and delta-catenin) may underlie our findings that antioestrogens can markedly stimulate migratory behaviour when tumour intercellular contacts are compromised. Based on our promising studies selectively inhibiting EGFR (gefitinib), NFkappaB (parthenolide) or CD59 (neutralising antibody) together with antioestrogens, we propose that co-targeting strategies could markedly improve anti-tumour activity (notably enhancing cell kill) during the antihormone-responsive phase. Furthermore, subverting those induced signalling genes that are retained into resistance (e.g. EGFR, NFkappaB, HER2) may prove valuable in this state. Alongside future deciphering and targeting of genes underlying antioestrogen-promoted invasiveness, embracing of intelligent combination strategies could significantly extend patient survival.
Insights
Breast cancer cells resist antihormone therapy by activating alternative signaling pathways, such as epidermal growth factor receptor (EGFR). Targeting these pathways alongside antihormones can improve treatment efficacy and overcome resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer treatment often involves antihormones targeting the oestrogen receptor alpha (ER).
- Complete inhibition of breast cancer by antihormones is uncommon due to cellular resistance mechanisms.
- ER blockade can trigger compensatory signaling pathways that limit therapeutic effectiveness.
Purpose of the Study:
- To investigate the molecular mechanisms by which breast cancer cells develop resistance to antihormone therapy.
- To identify specific signaling genes induced by antihormones that contribute to treatment resistance.
- To explore combination strategies targeting both ER and induced resistance pathways for improved breast cancer treatment.
Main Methods:
- Utilized responsive breast cancer models to study cellular responses to antihormone therapy.
- Employed microarrays to identify genes upregulated by antihormones.
- Investigated the role of specific induced genes (e.g., EGFR, NFkappaB, CD59) in mediating resistance and promoting invasiveness.
- Conducted studies combining antihormones with targeted inhibitors (e.g., gefitinib, parthenolide, anti-CD59 antibody).
Main Results:
- Antihormone treatment induces the expression of oestrogen-repressed genes, including EGFR, which promotes cell survival and resistance.
- Upregulated genes such as NFkappaB, Bag1, 14-3-3zeta, HER2, and Lyn attenuate growth inhibition.
- Some induced genes, like CD59, may facilitate immune evasion, while others, like NFkappaB, promote invasiveness and migration.
- Combination therapies targeting EGFR, NFkappaB, or CD59 with antihormones showed enhanced anti-tumour activity and improved cell kill.
Conclusions:
- Breast cancer cells exhibit significant flexibility in recruiting alternative signaling pathways to counteract antihormone therapy.
- Targeting induced signaling pathways like EGFR, NFkappaB, and CD59 concurrently with antihormones can overcome resistance and enhance anti-tumour effects.
- Combination strategies hold promise for improving therapeutic outcomes and extending patient survival in breast cancer treatment.
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