Academic Department of Biochemistry, Royal Marsden Foundation Trust, London, UK; Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
Mol Cell Endocrinol. 2014 Jan 25;382(1):683-694. doi: 10.1016/j.mce.2013.09.038. Epub 2013 Oct 9.
Oestrogens (E) and oestrogen receptor alpha (ERα) play fundamental roles in the development and progression of more than three-quarters of breast cancers (BC). The ability to influence the natural history of BC by hormonal manipulation is well established and endocrine therapies represent the cornerstone of systemic management for women with ERα-positive disease. Endocrine agents abrogate oestrogenic signalling through distinct and incompletely overlapping mechanisms, either impeding the transcriptional activity of ERα or diminishing E-synthesis. In post-menopausal women, E-production is chiefly attributable to the enzymatic conversion of androgens in extra-gonadal tissues by the cytochrome P-450 superfamily member aromatase. Greater understanding of steroid biosynthesis has underpinned rational drug design and pharmacological development of potent and specific aromatase inhibitors (AIs). Contemporary agents induce profound E-suppression in post-menopausal women and are first-line neo-adjuvant, adjuvant and metastatic therapies, with greater efficacy and tolerability than tamoxifen. The principal qualifier for endocrine treatment, including AIs, remains ERα expression. However, it is increasingly apparent that ERα expression is not synonymous with sensitivity to treatment and insufficient to account for the considerable heterogeneity of response. Better predictive biomarkers of de novo resistance are required to improve patient selection and identify those poor-responders who may benefit from alternative or additional systemic treatment from the outset. Among patients who do respond well initially, many relapse during their clinical course and there is also an unmet need for biomarkers of acquired resistance. The majority of women who relapse on AIs continue to express functional ERα which remains a legitimate target for second-line endocrine therapy. Understanding and overcoming acquired resistance to AIs requires a greater appreciation of ERα biology and the mechanisms though which E-dependence can be subverted. In this article, we review the impact of therapeutic E-deprivation on the natural history of ERα-positive breast cancer. Consideration is given to established and emerging biomarkers and/or determinants of response and resistance to E-deprivation. In vitro and in vivo evidence of the molecular mechanisms underpinning the transition from sensitivity to resistance are reviewed in the context of current models of ERα activity and their potential translational relevance.
雌激素（E）和雌激素受体 alpha（ERα）在超过四分之三的乳腺癌（BC）的发展和进展中发挥着基本作用。通过激素操纵影响 BC 的自然史的能力已得到充分确立，内分泌治疗是 ERα阳性疾病女性系统管理的基石。内分泌剂通过不同且不完全重叠的机制消除雌激素信号，要么阻碍 ERα 的转录活性，要么减少 E 合成。在绝经后妇女中，E 的产生主要归因于细胞色素 P-450 超家族成员芳香酶在性腺外组织中对雄激素的酶促转化。对类固醇生物合成的更深入了解为合理的药物设计和有效的、特异性的芳香酶抑制剂（AIs）的药理学发展奠定了基础。目前的药物在绝经后妇女中引起强烈的 E 抑制作用，是新辅助、辅助和转移性治疗的一线药物，其疗效和耐受性优于他莫昔芬。内分泌治疗的主要标准，包括 AIs，仍然是 ERα 表达。然而，越来越明显的是，ERα 表达与治疗敏感性不同，不足以解释反应的显著异质性。需要更好的预测新辅助耐药的生物标志物，以改善患者选择，并确定那些从一开始就可能受益于替代或额外的全身治疗的不良反应者。在最初反应良好的患者中，许多在其临床过程中复发，并且还需要获得性耐药的生物标志物。在 AI 复发的大多数女性中，仍然表达功能性 ERα，这仍然是二线内分泌治疗的合理靶点。了解和克服对 AIs 的获得性耐药需要更好地了解 ERα 生物学以及可以颠覆 E 依赖性的机制。在本文中，我们回顾了治疗性 E 剥夺对 ERα 阳性乳腺癌自然史的影响。考虑了对 E 剥夺的反应和耐药性的既定和新兴生物标志物和/或决定因素。在当前的 ERα 活性模型及其潜在的转化相关性的背景下，回顾了支持从敏感性向耐药性转变的分子机制的体外和体内证据。
