Androgens are produced locally in breast carcinoma tissues by androgen‑producing enzymes such as 5α‑reductase type 1 (5αRed1) and affect not only breast cancer cells but the tumor microenvironment as well. Tumor‑associated macrophages (TAMs) are primary components of the tumor microenvironment and contribute to tumor progression. Although previous studies suggest that androgen/androgen receptor (AR) signaling in macrophages has important roles in human diseases, androgen action on TAMs has remained largely unknown. We immunolocalized macrophage marker CD163 as well as AR and 5αRed1 in 116 breast carcinomas and correlated them with clinicopathological parameters and clinical outcomes. Moreover, we examined the roles of androgens on macrophages in breast cancer progression using cell lines 4T1 (mouse breast cancer) and RAW264.7 (macrophage) in a tumor‑bearing female BALB/c mouse model. Double immunohistochemistry revealed that AR was sporadically expressed in the macrophages in breast carcinoma tissues. Macrophage infiltration was significantly correlated with an aggressive phenotype of breast carcinomas and worse prognosis, especially in the 5αRed1‑positive group. In a sphere‑forming assay using 4T1 and RAW‑AR cells, which stably express AR, the sphere size was significantly increased due to androgens when 4T1 cells were cocultured with RAW‑AR cells. Furthermore, in vivo experiments revealed that tumor growth and Ki67, a cell proliferation marker, were increased when androgens were stably produced in breast cancer cells and AR was expressed in macrophages. In conclusion, AR is expressed in intratumoral macrophages and is associated with an aggressive phenotype of breast carcinomas, especially when breast cancer cells actively produce androgens. Thus, androgens may enhance the ability of macrophages to promote breast cancer progression.

中文翻译：

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雄激素增强肿瘤内巨噬细胞促进乳腺癌进展的能力。

雄激素在乳腺癌组织中由产生雄激素的酶如 5α-还原酶 1 (5αRed1) 局部产生，不仅影响乳腺癌细胞，而且影响肿瘤微环境。肿瘤相关巨噬细胞 (TAM) 是肿瘤微环境的主要组成部分，有助于肿瘤进展。尽管之前的研究表明巨噬细胞中的雄激素/雄激素受体 (AR) 信号传导在人类疾病中具有重要作用，但雄激素对 TAM 的作用在很大程度上仍然未知。我们免疫定位了 116 例乳腺癌中的巨噬细胞标记物 CD163 以及 AR 和 5αRed1，并将它们与临床病理参数和临床结果相关联。此外，我们使用细胞系 4T1（小鼠乳腺癌）和 RAW264.4 检测了雄激素对巨噬细胞在乳腺癌进展中的作用。7（巨噬细胞）在荷瘤雌性 BALB/c 小鼠模型中。双免疫组化显示AR在乳腺癌组织中的巨噬细胞中零星表达。巨噬细胞浸润与乳腺癌的侵袭性表型和较差的预后显着相关，尤其是在 5αRed1 阳性组中。在使用稳定表达 AR 的 4T1 和 RAW-AR 细胞的球体形成试验中，当 4T1 细胞与 RAW-AR 细胞共培养时，由于雄激素，球体大小显着增加。此外，特别是在 5αRed1 阳性组中。在使用稳定表达 AR 的 4T1 和 RAW-AR 细胞的球体形成试验中，当 4T1 细胞与 RAW-AR 细胞共培养时，由于雄激素，球体大小显着增加。此外，特别是在 5αRed1 阳性组中。在使用稳定表达 AR 的 4T1 和 RAW-AR 细胞的球体形成试验中，当 4T1 细胞与 RAW-AR 细胞共培养时，由于雄激素，球体大小显着增加。此外，体内实验表明，当雄激素在乳腺癌细胞中稳定产生且 AR 在巨噬细胞中表达时，肿瘤生长和细胞增殖标志物 Ki67 增加。总之，AR 在肿瘤内巨噬细胞中表达，并且与乳腺癌的侵袭性表型相关，尤其是当乳腺癌细胞积极产生雄激素时。因此，雄激素可以增强巨噬细胞促进乳腺癌进展的能力。