Breast cancer, the most prevalent malignancy in women, often progresses to bone metastases, especially in older individuals. Dormancy, a critical aspect of bone-metastasized breast cancer cells (BCCs), enables them to evade treatment and recur. This dormant state is regulated by bone marrow mesenchymal stem cells (BMMSCs) through the secretion of various factors, including those associated with senescence. However, the specific mechanisms by which BMMSCs induce dormancy in BCCs remain unclear. To address this gap, a bone-specific senescence-accelerated murine model, SAMP6, was utilized to minimize confounding systemic age-related factors. Confirming senescence-accelerated osteoporosis, distinct BMMSC phenotypes were observed in SAMP6 mice compared to SAMR1 counterparts. Notably, SAMP6-BMMSCs exhibited premature senescence primarily due to telomerase activity loss and activation of the p21 signaling pathway. Furthermore, the effects of conditioned medium (CM) derived from SAMP6-BMMSCs versus SAMR1-BMMSCs on BCC proliferation were examined. Intriguingly, only CM from SAMP6-BMMSCs inhibited BCC proliferation by upregulating p21 expression in both MCF-7 and MDA-MB-231 cells. These findings suggest that the senescence-associated secretory phenotype (SASP) of BMMSCs suppresses BCC viability by inducing p21, a pivotal cell cycle inhibitor and tumor suppressor. This highlights a heightened susceptibility of BCCs to dormancy in a senescent microenvironment, potentially contributing to the increased incidence of breast cancer bone metastasis and recurrence observed with aging.

Graphical Abstract

中文翻译：

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骨髓间充质干细胞衰老相关的分泌表型抑制乳腺癌细胞的活力

乳腺癌是女性中最常见的恶性肿瘤，通常会进展为骨转移，尤其是在老年人中。休眠是骨转移乳腺癌细胞 (BCC) 的一个重要方面，使它们能够逃避治疗并复发。这种休眠状态由骨髓间充质干细胞 (BMMSC) 通过分泌各种因子（包括与衰老相关的因子）来调节。然而，BMMSCs 诱导 BCC 休眠的具体机制仍不清楚。为了解决这一差距，利用骨特异性加速衰老小鼠模型 SAMP6 来最大程度地减少与年龄相关的系统混杂因素。与 SAMR1 小鼠相比，在 SAMP6 小鼠中观察到不同的 BMMSC 表型，证实了衰老加速的骨质疏松症。值得注意的是，SAMP6-BMMSC 表现出过早衰老的主要原因是端粒酶活性丧失和 p21 信号通路激活。此外，还检查了源自 SAMP6-BMMSC 与 SAMR1-BMMSC 的条件培养基 (CM) 对 BCC 增殖的影响。有趣的是，只有来自 SAMP6-BMMSC 的 CM 通过上调 MCF-7 和 MDA-MB-231 细胞中的 p21 表达来抑制 BCC 增殖。这些发现表明，BMMSC 的衰老相关分泌表型 (SASP) 通过诱导 p21（一种关键的细胞周期抑制剂和肿瘤抑制因子）来抑制 BCC 活力。这凸显了基底细胞癌在衰老微环境中对休眠的敏感性增加，可能导致随年龄增长而观察到的乳腺癌骨转移和复发的发生率增加。

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