An abundance of tumor-associated macrophages has been shown to be an independent prognostic factor for a poor prognosis of human breast cancer (BC). Adipose tissue accounts for the largest proportion of the breast and has also been identified as an independent indicator of poor survival in BC. This study aims to elucidate if the influence of adipose tissue in BC might be mediated by macrophages. The roles of macrophages in the breast tumor-stroma (breast tumor stroma macrophages, BTSM) and macrophages in the surrounding adipose tissue (breast adipose tissue macrophages, BATM) were explored separately. Two hundred ninety-eight BC tissue samples were analyzed immunohistochemically. The number of macrophages was detected by CD68+ staining. The quantity of BATMs and BTSMs was correlated to clinical and pathological parameters as well as to disease-free survival (DFS) and overall survival (OS). The amounts of BATMs and BTSMs strongly correlated with each other (r = 0.5, p = 2.98E−15). The quantity of BTSMs, but not of BATMs, was significantly associated with the BC molecular subtype (p = 0.000011), and all triple-negative BC tumors contained high amounts of BTSMs. BATMs were negatively associated with DFS (p = 0.0332). Both BATMs (p = 0.000401) and BTSMs (p = 0.021) were negatively associated with OS in the Kaplan-Meier analysis, but only BATMs remained an independent factor in the multivariate Cox-regression analysis (HR = 4.464, p = 0.004). Combining prostaglandin E2 receptor 3 (EP3)-expression and the quantity of BATMs, a subgroup with an extremely poor prognosis could be identified (median OS 2.31 years in the “high BATMs/low EP3” subgroup compared to 11.42 years in the most favorable “low BATMs/high EP3” subgroup, p = 0.000002). Our findings suggest that BTSMs and BATMs seem to be involved differently in BC. Breast adipose tissue might contribute to the aggressiveness of BC via BATMs, which were independently associated with BC survival. BATMs’ role and occurrence might be functionally dependent on EP3, as a combination of both factors was strongly associated with survival. Targeting BATMs—eventually in combination with targeting the EP3-pathway—might be promising for future therapies.

中文翻译：

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与乳腺肿瘤基质巨噬细胞 (BTSM) 相比，乳腺脂肪组织巨噬细胞 (BATM) 与乳腺癌存活率的相关性更强

大量的肿瘤相关巨噬细胞已被证明是人类乳腺癌 (BC) 预后不良的独立预后因素。脂肪组织占乳房的最大比例，并且也被确定为 BC 生存率低的独立指标。本研究旨在阐明脂肪组织对 BC 的影响是否可能由巨噬细胞介导。巨噬细胞在乳腺肿瘤基质中的作用（乳腺肿瘤基质巨噬细胞，BTSM）和周围脂肪组织中的巨噬细胞（乳腺脂肪组织巨噬细胞，BATM）分别进行了探讨。298 个 BC 组织样本进行了免疫组织化学分析。通过CD68+染色检测巨噬细胞的数量。BATM 和 BTSM 的数量与临床和病理参数以及无病生存 (DFS) 和总生存 (OS) 相关。BATM 和 BTSM 的数量彼此密切相关（r = 0.5，p = 2.98E-15）。BTSM 的数量而非 BATM 的数量与 BC 分子亚型（p = 0.000011）显着相关，并且所有三阴性 BC 肿瘤都含有大量 BTSM。BATM 与 DFS 呈负相关（p = 0.0332）。在 Kaplan-Meier 分析中，BATMs (p = 0.000401) 和 BTSMs (p = 0.021) 都与 OS 呈负相关，但只有 BATMs 在多变量 Cox 回归分析中仍然是一个独立因素（HR = 4.464，p = 0.004）。结合前列腺素 E2 受体 3 (EP3) 表达和 BATM 的数量，可以确定预后极差的亚组（“高 BATM/低 EP3”亚组的中位 OS 为 2.31 年，而最有利的“低 BATM/高 EP3”亚组为 11.42 年，p = 0.000002）。我们的研究结果表明 BTSM 和 BATM 似乎在 BC 中的参与不同。乳腺脂肪组织可能通过 BATMs 促进 BC 的侵袭性，这与 BC 的存活率独立相关。BATM 的作用和发生可能在功能上取决于 EP3，因为这两个因素的组合与生存密切相关。靶向 BATMs——最终与靶向 EP3 通路相结合——可能对未来的治疗有希望。我们的研究结果表明 BTSM 和 BATM 似乎在 BC 中的参与不同。乳腺脂肪组织可能通过 BATMs 促进 BC 的侵袭性，这与 BC 的存活率独立相关。BATM 的作用和发生可能在功能上取决于 EP3，因为这两个因素的组合与生存密切相关。靶向 BATMs——最终与靶向 EP3 通路相结合——可能对未来的治疗有希望。我们的研究结果表明 BTSM 和 BATM 似乎在 BC 中的参与不同。乳腺脂肪组织可能通过 BATMs 促进 BC 的侵袭性，这与 BC 的存活率独立相关。BATM 的作用和发生可能在功能上取决于 EP3，因为这两个因素的组合与生存密切相关。靶向 BATMs——最终与靶向 EP3 通路相结合——可能对未来的治疗有希望。