The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer
The link between BRCA1/2 mutations and high susceptibility to breast cancer development has been well-established for years. However, the potential impact of BRCA1/2 mutations on the individual cell populations within the unique tumor microenvironment and their relation to breast cancer has been understudied. This review aims to provide significant insights into up-to-date knowledge about the role of BRCA1/2-mutated tumor microenvironment and possible mechanisms by which it interacts with and promotes breast cancer development and progression. Uncovering and exposing these mechanisms of the aberrant microenvironment might provide more effective strategies for treatment of germline mutation-carrying breast cancer patients.
Taking into account the factors of high incidence rate, prevalence and mortality, breast cancer represents a crucial social and economic burden. Most cases of breast cancer develop as a consequence of somatic mutations accumulating in mammary epithelial cells throughout lifetime and approximately 5–10% can be ascribed to monogenic predispositions. Even though the role of genetic predispositions in breast cancer is well described in the context of genetics, very little is known about the role of the microenvironment carrying the same aberrant cells impaired by the germline mutation in the breast cancer development and progression. Based on the clinical observations, carcinomas carrying mutations in hereditary tumor-suppressor genes involved in maintaining genome integrity such as BRCA1/2 have worse prognosis and aggressive behavior. One of the mechanisms clarifying the aggressive nature of BRCA-associated tumors implies alterations within the surrounding adipose tissue itself. The objective of this review is to look at the role of BRCA1/2 mutations in the context of breast tumor microenvironment and plausible mechanisms by which it contributes to the aggressive behavior of the tumor cells
考虑到高发病率、患病率和死亡率等因素，乳腺癌是一项至关重要的社会和经济负担。大多数乳腺癌病例是由于体细胞突变在整个生命周期中在乳腺上皮细胞中积累的结果，大约 5-10% 可归因于单基因易感性。尽管遗传易感性在乳腺癌中的作用在遗传学背景下得到了很好的描述，但对于携带受种系突变损害的相同异常细胞的微环境在乳腺癌发展和进展中的作用知之甚少。根据临床观察，携带参与维持基因组完整性的遗传性肿瘤抑制基因突变的癌症，如BRCA1/2预后较差，具有攻击性行为。阐明BRCA相关肿瘤侵袭性的机制之一意味着周围脂肪组织本身的改变。本综述的目的是研究BRCA1/2突变在乳腺肿瘤微环境中的作用，以及它促成肿瘤细胞攻击行为的可能机制。
The tumor microenvironment, as another dimension of tumor complexity, has been acknowledged as an important hallmark of cancer more than decade ago. In many aspects it dictates and impacts the tumor behavior and treatment response. However, how the various cells residing in the TME of germline BRCA1/BRCA2-deficient breast tumors that are equally impaired by the same germline mutation contribute to the pathogenesis of the hereditary breast cancer has not been consistently addressed. Results of several experimental and preclinical studies unequivocally point to the need to study not only the tumor epithelial cells, but also the wider concept of TME in which the BRCA genes exert their functions. This review aimed to provide significant insights into up-to-date knowledge about the role of BRCA1/2-mutated tumor microenvironment and possible mechanisms by which it interacts with and promotes breast cancer development and progression. Uncovering and exposing these mechanisms of the aberrant microenvironment might provide more effective strategies for treatment of germline mutation-carrying breast cancer patients.
肿瘤微环境作为肿瘤复杂性的另一个维度，在十多年前已被公认为癌症的重要标志。在许多方面，它决定并影响肿瘤行为和治疗反应。然而，存在于生殖系BRCA1/BRCA2缺陷型乳腺肿瘤的 TME 中的各种细胞，它们同样受到相同的生殖系突变的损害，如何导致遗传性乳腺癌的发病机制尚未得到一致解决。几项实验和临床前研究的结果明确指出，不仅需要研究肿瘤上皮细胞，还需要研究更广泛的 TME 概念，其中BRCA基因发挥其功能。本综述旨在提供有关BRCA1/2突变肿瘤微环境作用的最新知识及其与乳腺癌发生和进展相互作用并促进其发生和进展的可能机制的重要见解。揭示和揭示异常微环境的这些机制可能为治疗携带种系突变的乳腺癌患者提供更有效的策略。
关键词： 乳腺癌,肿瘤微环境,BRCA1/2突变,基质细胞,上皮间质转化,血管生成, breast cancer,tumor microenvironment,BRCA1/2 mutations,stromal cells,epithelial-to-mesenchymal transition, angiogenesis