Breast cancer is the second leading cause of cancer-related death in women and is a complex disease with high intratumoral and intertumoral heterogeneity. Such heterogeneity is a major driving force behind failure of current therapies and development of resistance. Due to the limitations of conventional therapies and inevitable emergence of acquired drug resistance (chemo and endocrine) as well as radio resistance, it is essential to design novel therapeutic strategies to improve the prognosis for breast cancer patients. Deregulated Notch signaling within the breast tumor and its tumor microenvironment (TME) is linked to poor clinical outcomes in treatment of resistant breast cancer. Notch receptors and ligands are also important for normal mammary development, suggesting the potential for conserved signaling pathways between normal mammary gland development and breast cancer. In this review, we focus on mechanisms by which Notch receptors and ligands contribute to normal mammary gland development and breast tumor progression. We also discuss how complex interactions between cancer cells and the TME may reduce treatment efficacy and ultimately lead to acquired drug or radio resistance. Potential combinatorial approaches aimed at disrupting Notch- and TME-mediated resistance that may aid in achieving in an improved patient prognosis are also highlighted.

中文翻译：

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Notch 信号在乳腺癌中的许多方面：克服治疗耐药性

乳腺癌是女性癌症相关死亡的第二大原因，是一种具有高度肿瘤内和肿瘤间异质性的复杂疾病。这种异质性是当前疗法失败和耐药性发展的主要驱动力。由于传统疗法的局限性和获得性耐药（化学和内分泌）以及放射耐药性的不可避免出现，设计新的治疗策略以改善乳腺癌患者的预后至关重要。乳腺肿瘤及其肿瘤微环境 (TME) 中失调的 Notch 信号与耐药乳腺癌治疗的不良临床结果有关。Notch 受体和配体对于正常的乳腺发育也很重要，表明正常乳腺发育和乳腺癌之间存在保守信号通路的可能性。在这篇综述中，我们重点关注 Notch 受体和配体促进正常乳腺发育和乳腺肿瘤进展的机制。我们还讨论了癌细胞和 TME 之间复杂的相互作用如何降低治疗效果并最终导致获得性药物或放射抗性。还强调了旨在破坏 Notch 和 TME 介导的耐药性的潜在组合方法，这些方法可能有助于改善患者的预后。我们还讨论了癌细胞和 TME 之间复杂的相互作用如何降低治疗效果并最终导致获得性药物或放射抗性。还强调了旨在破坏 Notch 和 TME 介导的耐药性的潜在组合方法，这些方法可能有助于改善患者的预后。我们还讨论了癌细胞和 TME 之间复杂的相互作用如何降低治疗效果并最终导致获得性药物或放射抗性。还强调了旨在破坏 Notch 和 TME 介导的耐药性的潜在组合方法，这些方法可能有助于改善患者的预后。