Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty.
Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty.
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DOI：
10.1515/hmbci.2010.031
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发表时间：
2010-06
影响因子：
1
通讯作者：
Hilakivi-Clarke L
中科院分区：
文献类型：
--
作者：
Shajahan AN;Goel S;de Assis S;Yu B;Clarke R;Hilakivi-Clarke L
雌激素暴露时大鼠乳腺的发育阶段决定了暴露是否增加或减少以后的乳腺癌风险。例如，子宫内暴露于17β-雌二醇（E2）增加，而青春期前暴露于这种激素降低了致癌物诱导的乳腺肿瘤的易感性。E2通过与caveolin-1（CAV 1）相互作用介导其作用，CAV 1是乳腺癌中假定的肿瘤抑制基因。与溶剂对照组相比，子宫内暴露于E2的2月龄大鼠的乳腺组织中CAV 1水平降低，而青春期前E2暴露水平升高。在子宫内暴露于E2的大鼠乳腺中，CAV 1低表达与细胞增殖和雌激素受体α表达增加以及细胞凋亡减少相关。与此相反，高CAV 1表达与减少细胞增殖和细胞周期蛋白D1和磷酸化Akt水平，并在青春期前暴露于E2的大鼠乳腺细胞凋亡增加。为了支持CAV 1作为多种促生长信号蛋白的负调节剂的作用，我们检测到青春期前暴露于E2的大鼠中Src和ErbB 2水平降低。因此，乳腺发育过程中的雌激素暴露影响CAV 1的表达和功能，其方式与观察到的乳腺肿瘤发生易感性变化一致。
Developmental stage of rat mammary gland at the time of estrogen exposure determines whether the exposure increases or reduces later breast cancer risk. For example, in utero exposure to 17β-estradiol (E2) increases, whereas prepubertal exposure to this hormone decreases susceptibility of developing carcinogen-induced mammary tumors. E2 mediates its actions by interacting with caveolin-1 (CAV1), a putative tumor suppressor gene in breast cancer. Mammary tissues from 2-month-old rats exposed to E2 in utero contained decreased levels of CAV1, whereas prepubertal E2 exposure increased the levels, when compared to vehicle controls. Low CAV1 expression was associated with increased cell proliferation and estrogen receptor α expression, and reduced apoptosis in the mammary glands of rats exposed to E2 in utero. In contrast, high CAV1 expression correlated with reduced cell proliferation and cyclin D1 and phospho-Akt levels, and increased apoptosis in the mammary glands of rats exposed to E2 during prepuberty. In support of the role of CAV1 as a negative regulator of a variety of pro-growth signaling proteins, we detected decreased levels of Src and ErbB2 in rats exposed to E2 during prepuberty. Thus, estrogen exposure during mammary gland development affects the expression and function of CAV1 in a manner consistent with observed changes in susceptibility to mammary tumorigenesis.