Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy

Bleach, Rachel; Madden, Stephen F.; Hawley, James; Charmsaz, Sara; Selli, Çiğdem; Sheehan, Katherine M.; Young, Leonie S.; Sims, Andrew H.; Souček, Pavel; Hill, Arnold D.; McIlroy, Marie

doi:10.1158/1078-0432.ccr-20-4135

Cited by 5 publications

(2 citation statements)

References 49 publications

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“…The expression of prostate-specific antigen, a representative androgen-induced gene, is increased in recurrent tissues. In addition, a recent transcriptional analysis revealed an increased ratio of AR:ERα signaling pathway activities in patients failing AI therapy ( Bleach et al 2021 ). These findings suggest that increased androgen action is closely linked to AI resistance.…”

Section: Androgens and Therapeutic Resistance In Breast Cancermentioning

confidence: 99%

Diverse role of androgen action in human breast cancer

et al. 2022

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Breast cancer is a hormone-dependent cancer and sex steroids play a pivotal role in breast cancer progression. Estrogens are strongly associated with breast cancers, and the estrogen receptor (estrogen receptor α; ERα) is expressed in 70–80% of human breast carcinoma tissues. Although antiestrogen therapies (endocrine therapies) have significantly improved clinical outcomes in ERα-positive breast cancer patients, some patients experience recurrence after treatment. In addition, patients with breast carcinoma lacking ERα expression do not benefit from endocrine therapy. The androgen receptor (AR) is also expressed in >70% of breast carcinoma tissues. Growing evidence supports this novel therapeutic target for the treatment of triple negative breast cancers (TNBCs) that lack ERα, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and ERα-positive breast cancers, which are resistant to conventional endocrine therapy. However, the clinical significance of AR expression is still controversial and the biological function of androgens in breast cancers is unclear. In this review, we focus on the recent findings concerning androgen action in breast cancers and the contributions of androgens to improved breast cancer therapy.

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Section: Androgens and Therapeutic Resistance In Breast Cancermentioning

confidence: 99%

Diverse role of androgen action in human breast cancer

et al. 2022

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“…A recent trial NCT02007512 using the AI exemestane, with or without enzalutamide, in patients with ER+ advanced/metastatic disease found that high levels of AR and low levels of ESR1 were associated with the significantly greater benefit of enzalutamide 20 . These complexities emphasize the importance of clinical context and hormonal milieu when considering AR action in BC 21 . Clearly, AR does influence BC biology, and high AR relative to ER levels can serve as an independent predictor of response to anti-estrogen therapies, perhaps by identifying tumors poised to escape ER-directed therapies and switch to survival dependent on androgens and AR.…”

Section: Introductionmentioning

confidence: 99%

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2− advanced breast cancer

et al. 2023

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This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2− breast cancer (BC). Eligible patients were women with ECOG 0–2, ER+/HER2− measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46–87); PS 1 (0–1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2–52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2− BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

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Extra-nuclear and cytoplasmic steroid receptor signalling in hormone dependent cancers

Agbana,

McIlroy

2024

The Journal of Steroid Biochemistry and Molecular Biology

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Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy

Cited by 5 publications

References 49 publications

Diverse role of androgen action in human breast cancer

Diverse role of androgen action in human breast cancer

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2− advanced breast cancer

Extra-nuclear and cytoplasmic steroid receptor signalling in hormone dependent cancers

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