Control of mammary stem cell function by steroid hormone signalling
Control of mammary stem cell function by steroid hormone signalling
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DOI：
10.1038/nature09027
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发表时间：
2010-06-10
期刊：
影响因子：
64.8
通讯作者：
Visvader, Jane E.
中科院分区：
文献类型：
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作者：
Asselin-Labat, Marie-Liesse;Vaillant, Francois;Visvader, Jane E.
卵巢激素雌激素和孕激素深刻影响乳腺癌风险（1-3），支持内分泌疗法治疗乳腺癌的益处（4）。通过卵巢消融或化学预防策略调节其作用也可显著降低乳腺癌发病率（5，6）。相反，短期内与怀孕相关的乳腺癌风险增加（7）。然而，这些观察结果背后的细胞机制还不清楚。在这里，我们证明了小鼠乳腺干细胞（MaSC）（8，9）对类固醇激素信号传导具有高度响应性，尽管缺乏雌激素和孕酮受体（10）。卵巢切除术显着减少MaSC的数量和生长潜力在体内，而MaSC活性增加，雌激素加孕酮治疗的小鼠。值得注意的是，即使用芳香酶抑制剂来曲唑治疗三周也足以减少MaSC池。相比之下，妊娠导致MaSC数量一过性增加11倍，可能通过RANK配体的旁分泌信号传导介导。增加的MaSC库表明，伴随怀孕的乳腺癌发病率短期增加的细胞基础。这些发现进一步表明，乳腺癌化学预防可能部分通过抑制MaSC功能来实现。
The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk(1-3), underpinning the benefit of endocrine therapies in the treatment of breast cancer(4). Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence(5,6). Conversely, there is an increased risk of breast cancer associated with pregnancy in the short term(7). The cellular mechanisms underlying these observations, however, are poorly defined. Here we demonstrate that mouse mammary stem cells (MaSCs)(8,9) are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors(10). Ovariectomy markedly diminished MaSC number and outgrowth potential in vivo, whereas MaSC activity increased in mice treated with oestrogen plus progesterone. Notably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. In contrast, pregnancy led to a transient 11-fold increase in MaSC numbers, probably mediated through paracrine signalling from RANK ligand. The augmented MaSC pool indicates a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy. These findings further indicate that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.