ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.
ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.
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DOI：
10.1186/s13058-017-0893-7
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发表时间：
2017-09-08
期刊：
影响因子：
--
通讯作者：
Cook RS
中科院分区：
文献类型：
--
作者：
Williams MM;Vaught DB;Joly MM;Hicks DJ;Sanchez V;Owens P;Rahman B;Elion DL;Balko JM;Cook RS
在怀孕期间，随着乳腺准备合成和向新生儿递送乳汁，腔乳腺上皮细胞（MEC）亚群响应于激活STAT5A的全身性激素信号而迅速增殖。虽然受体酪氨酸激酶ErbB4是妊娠期间MEC中STAT5A激活所必需的，但ErbB3（ErbB4的异二聚体伴侣和磷脂酰肌醇-3激酶（PI3K）信号传导的激活剂）如何促进乳腺的催乳扩张尚不清楚。我们评估mRNA表达水平的表达芯片小鼠乳腺收获整个怀孕和哺乳期。为了研究ErbB3在乳腺泌乳中的作用，我们使用表达WAP驱动的Cre重组酶的转基因小鼠来产生小鼠模型，其中条件性ErbB3消融特异性地发生在肺泡乳腺上皮细胞（aMEC）中。从整个妊娠期间分离的小鼠MEC的RNA分析显示，在妊娠中期至晚期，aMEC快速增殖并进行分化以支持产奶的时间点，Erbb3诱导强烈。与ErbB3 WT母鼠哺育的窝仔相比，ErbB3 KO母鼠哺育的窝仔体重显著更轻。进一步的分析显示，在妊娠晚期，上皮含量显著减少，aMEC增殖减少，aMEC细胞死亡增加。与ErbB3通过PI3K/Akt途径激活细胞存活的有效能力一致，我们发现ErbB3 KO样品中Akt磷酸化受损，以及STAT5A表达受损，STAT5A是乳糖生成的主要调节因子。组成性活性Akt在ErbB3耗尽的aMEC中挽救细胞存活，但未能恢复STAT5A表达或活性。有趣的是，ErbB3 KO aMEC的生长和存活缺陷以及在ErbB3 KO MEC中观察到的Akt磷酸化、STAT5A活性和乳汁编码基因的表达在妊娠晚期和哺乳期第5天之间逐渐改善。我们发现ErbB3 KO乳腺中ErbB4活性的补偿性上调。增强的ErbB4表达减轻了aMEC中ErbB3消融的后果，而ErbB3和ErbB4两者的联合消融夸大了表型。这些研究表明，ErbB3和ErbB4一样，通过激活Akt和STAT5A（两个对泌乳至关重要的靶点），增强妊娠期间乳腺的催乳扩张和分化。本文的在线版本（doi：10.1186/s13058 - 017 - 0893 - 7）包含补充材料，可供授权用户使用。
During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland. We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs). Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 KO dams weighed significantly less when compared to litters nursed by ErbB3 WT dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 KO samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 KO aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 KO MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3 KO mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype. These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation. The online version of this article (doi:10.1186/s13058-017-0893-7) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.91.17.8132
发表时间：
1994-08-16
影响因子：
11.1
作者：
GUY, PM;PLATKO, JV;CARRAWAY, KL
通讯作者：
CARRAWAY, KL
STAT5激活和乳腺分化需要AKT。
DOI：
10.1186/bcr2640
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chen CC;Boxer RB;Stairs DB;Portocarrero CP;Horton RH;Alvarez JV;Birnbaum MJ;Chodosh LA
通讯作者：
Chodosh LA
影响因子：
64.8
作者：
Asselin-Labat, Marie-Liesse;Vaillant, Francois;Visvader, Jane E.
通讯作者：
Visvader, Jane E.
DOI：
10.1093/jnci/djj267
发表时间：
2006-07-19
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Asselin-Labat, Marie-Liesse;Shackleton, Mark;Lindeman, Geoffrey J.
通讯作者：
Lindeman, Geoffrey J.
影响因子：
8
作者：
Jones, FE;Stern, DF
通讯作者：
Stern, DF