Role of ERα in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis
Role of ERα in the differential response of Stat5a loss in susceptibility to mammary preneoplasia and DMBA-induced carcinogenesis
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DOI：
10.1093/carcin/bgq048
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发表时间：
2010-06-01
期刊：
影响因子：
4.7
通讯作者：
Furth, Priscilla A.
中科院分区：
文献类型：
--
作者：
Miermont, Anne M.;Parrish, Angela R.;Furth, Priscilla A.
雌激素信号失调显然与乳腺癌病理生理学有关，尽管信号转导子和转录激活子（Stat）5a（正常乳腺发育不可或缺）的作用尚不清楚。将乳腺上皮细胞靶向雌激素受体α（ER α）表达失调的小鼠模型[乳腺上皮中的条件性ER α（CERM）]与携带Stat 5a生殖系缺失[Stat 5a-/-]的小鼠杂交，以研究乳腺组织中ER α和Stat 5a之间的相互作用。产生CERM、CERM/Stat 5a +/-、CERM/Stat 5a-/-、Stat 5a +/-、Stat 5a-/-和野生型（WT）小鼠以测试ER α和Stat 5a在暴露于和不暴露于化学致癌物7，12-二甲基苯并[a]蒽（DMBA）的情况下对青春期分化和癌症进展的作用。只有CERM/Stat 5a-/-小鼠表现出延迟的青春期终末芽分化。在没有DMBA暴露的情况下，Stat 5a缺失消除了ER α引发的增生性肺泡结节（HAN）的发展，并且类似地，Stat 5a-/-小鼠没有发展HAN。然而，尽管Stat 5a丢失仍然降低了DMBA暴露后ER α启动的HAN患病率，但与WT相比，Stat 5a丢失而ER α未失调与HAN患病率增加相关。在所有含CERM的基因型（CERM、CERM/Stat 5a +/-、CERM/Stat 5a-/-）中发现进展为ER α（+）和ER α（-）腺癌，在Stat 5a-/-基因型中发现进展为ER α（+）腺癌。乳腺上皮细胞增殖指数仅在CERM小鼠中增加，与Stat 5a丢失无关。总之，Stat 5a与ER α失调合作，延缓青春期乳腺分化，并促进ER α启动的癌前病变，但其损失并不能阻止浸润性癌的发展。此外，在不存在ER α失调的情况下，Stat 5a丢失与DMBA暴露后HAN和浸润性癌症的发展相关。
Deregulated estrogen signaling is evidently linked to breast cancer pathophysiology, although the role of signal transducer and activator of transcription (Stat)5a, integral to normal mammary gland development, is less clear. A mouse model of mammary epithelial cell-targeted deregulated estrogen receptor alpha (ER alpha) expression [conditional ER alpha in mammary epithelium (CERM)] was crossed with mice carrying a germ line deletion of Stat5a [Stat5a-/-] to investigate interactions between ER alpha and Stat5a in mammary tissue. CERM, CERM/Stat5a+/-, CERM/Stat5a-/-, Stat5a+/-, Stat5a-/- and wild-type (WT) mice were generated to test the roles of ER alpha and Stat5a on pubertal differentiation and cancer progression with and without exposure to the chemical carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Only CERM/Stat5a-/- mice demonstrated delayed pubertal terminal end bud differentiation. Without DMBA exposure, Stat5a loss abrogated ER alpha-initiated hyperplastic alveolar nodule (HAN) development and, similarly, Stat5a-/- mice did not develop HANs. However, although Stat5a loss still reduced ER alpha-initiated HAN prevalence following DMBA exposure, Stat5a loss without deregulated ER alpha was associated with an increased HAN prevalence compared with WT. Progression to ER alpha(+) and ER alpha(-) adenocarcinoma was found in all CERM-containing genotypes (CERM, CERM/Stat5a+/-, CERM/Stat5a-/-) and ER alpha(+) adenocarcinoma in the Stat5a-/- genotype. The mammary epithelial cell proliferative index was increased only in CERM mice independent of Stat5a loss. No differences in apoptotic indices were found. In summary, Stat5a cooperated with deregulated ER alpha in retarding pubertal mammary differentiation and contributed to ER alpha-initiated preneoplasia, but its loss did not prevent development of invasive cancer. Moreover, in the absence of deregulated ER alpha, Stat5a loss was associated with development of both HANs and invasive cancer following DMBA exposure.