Developmental stage determines the effects of MYC in the mammary epithelium
Developmental stage determines the effects of MYC in the mammary epithelium
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DOI：
10.1242/dev.01655
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发表时间：
2005-03-01
期刊：
影响因子：
4.6
通讯作者：
Chodosh, LA
中科院分区：
文献类型：
--
作者：
Blakely, CM;Sintasath, L;Chodosh, LA
流行病学研究结果表明，特定致癌刺激的后果取决于暴露时靶组织的发育状态。这在乳腺中尤其明显，在乳腺中，暴露于致癌刺激物的年龄和第一次足月妊娠的时间可以显着改变患乳腺癌的风险。与此类似，激活癌基因（如MYC）的生物学后果可能受到细胞谱系和细胞环境方面的细胞背景的影响。鉴于此，我们假设乳腺中异常MYC激活的后果可能由MYC暴露时腺体的发育状态决定。为了直接验证这一假设，我们使用了强力霉素诱导的转基因小鼠模型，在乳腺发育的不同阶段过表达MYC。使用该模型，我们发现MYC抑制产后泌乳的能力完全是由于其在妊娠中期特定的72小时窗口内的激活;相比之下，MYC在72小时窗口之前或之后的激活对产后泌乳几乎没有影响。令人惊讶的是，我们发现MYC不会通过抑制乳腺上皮分化来阻断产后泌乳，而是通过促进妊娠期间的分化和早熟泌乳，这反过来又导致腺体过早退化。我们进一步表明，MYC促进乳腺上皮分化的这种发育阶段特异性能力与其下调小窝蛋白I并以发育阶段特异性方式激活Stat 5的能力密切相关。我们的研究结果为癌基因激活的发育阶段特异性效应提供了独特的体内分子证据，以及将MYC与Jak 2-Stat 5信号通路激活联系起来的第一个证据。
Epidemiological findings suggest that the consequences of a given oncogenic stimulus vary depending upon the developmental state of the target tissue at the time of exposure. This is particularly evident in the mammary gland, where both age at exposure to a carcinogenic stimulus and the timing of a first full-term pregnancy can markedly alter the risk of developing breast cancer. Analogous to this, the biological consequences of activating oncogenes, such as MYC, can be influenced by cellular context both in terms of cell lineage and cellular environment. In light of this, we hypothesized that the consequences of aberrant MYC activation in the mammary gland might be determined by the developmental state of the gland at the time of MYC exposure. To test this hypothesis directly, we have used a doxycycline-inducible transgenic mouse model to overexpress MYC during different stages of mammary gland development. Using this model, we find that the ability of MYC to inhibit postpartum lactation is due entirely to its activation within a specific 72-hour window during mid-pregnancy; by contrast, MYC activation either prior to or following this 72-hour window has little or no effect on postpartum lactation. Surprisingly, we find that MYC does not block postpartum lactation by inhibiting mammary epithelial differentiation, but rather by promoting differentiation and precocious lactation during pregnancy, which in turn leads to premature involution of the gland. We further show that this developmental stage-specific ability of MYC to promote mammary epithelial differentiation is tightly linked to its ability to downregulate caveolin I and activate Stat5 in a developmental stage-specific manner. Our findings provide unique in vivo molecular evidence for developmental stage-specific effects of oncogene activation, as well as the first evidence linking MYC with activation of the Jak2-Stat5 signaling pathway.