Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Oglesby Cancer Research Building, Wilmslow Road, Manchester, M20 4GJ, United Kingdom.
Manchester Breast Centre, University of Manchester, Wilmslow Road, Manchester, M20 4GJ, United Kingdom.
J Mammary Gland Biol Neoplasia. 2024 May 2;29(1):9. doi: 10.1007/s10911-024-09562-4.
Improved screening and treatment have decreased breast cancer mortality, although incidence continues to rise. Women at increased risk of breast cancer can be offered risk reducing treatments, such as tamoxifen, but this has not been shown to reduce breast cancer mortality. New, more efficacious, risk-reducing agents are needed. The identification of novel candidates for prevention is hampered by a lack of good preclinical models. Current patient derived in vitro and in vivo models cannot fully recapitulate the complexities of the human tissue, lacking human extracellular matrix, stroma, and immune cells, all of which are known to influence therapy response. Here we describe a normal breast explant model utilising a tuneable hydrogel which maintains epithelial proliferation, hormone receptor expression, and residency of T cells and macrophages over 7 days. Unlike other organotypic tissue cultures which are often limited by hyper-proliferation, loss of hormone signalling, and short treatment windows (< 48h), our model shows that tissue remains viable over 7 days with none of these early changes. This offers a powerful and unique opportunity to model the normal breast and study changes in response to various risk factors, such as breast density and hormone exposure. Further validation of the model, using samples from patients undergoing preventive therapies, will hopefully confirm this to be a valuable tool, allowing us to test novel agents for breast cancer risk reduction preclinically.
尽管乳腺癌死亡率有所下降,但由于筛查和治疗水平的提高,发病率仍在继续上升。可以为乳腺癌高危女性提供风险降低治疗,例如他莫昔芬,但这并不能降低乳腺癌死亡率。需要新的、更有效的降低风险的药物。由于缺乏良好的临床前模型,新型预防候选药物的鉴定受到阻碍。目前的基于患者的体外和体内模型不能完全再现人类组织的复杂性,缺乏人类细胞外基质、基质和免疫细胞,所有这些都已知会影响治疗反应。在这里,我们描述了一种利用可调谐水凝胶的正常乳腺外植体模型,该模型可维持上皮细胞增殖、激素受体表达以及 T 细胞和巨噬细胞在 7 天内的驻留。与其他通常受到过度增殖、激素信号丧失和较短治疗窗口(<48 小时)限制的器官型组织培养不同,我们的模型表明组织在 7 天内保持存活,没有出现这些早期变化。这为模拟正常乳腺和研究对各种风险因素(如乳腺密度和激素暴露)的反应提供了一个强大而独特的机会。使用正在接受预防性治疗的患者样本进一步验证该模型,有望证实这是一种有价值的工具,使我们能够在临床前测试用于降低乳腺癌风险的新型药物。
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