FOXK2 transcription factor suppresses ERα-positive breast cancer cell growth through down-regulating the stability of ERα via mechanism involving BRCA1/BARD1.
FOXK2 transcription factor suppresses ERα-positive breast cancer cell growth through down-regulating the stability of ERα via mechanism involving BRCA1/BARD1.
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DOI：
10.1038/srep08796
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发表时间：
2015-03-05
影响因子：
4.6
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Liu Y;Ao X;Jia Z;Bai XY;Xu Z;Hu G;Jiang X;Chen M;Wu H
雌激素受体（ER）是乳腺癌发展的关键调节因子。鉴定调节ER功能的分子可能有助于开发更有效的乳腺癌治疗策略。在本研究中，我们发现叉头转录因子FOXK 2与ERα相互作用，并通过增强泛素介导的ERα降解来抑制ERα调节的转录活性。该过程涉及FOXK 2与ERα的E3泛素连接酶BRCA 1/BARD 1之间的相互作用。FOXK 2与BARD 1相互作用，并作为BRCA 1/BARD 1和ERα的支架蛋白，导致ERα降解增强，最终导致其转录活性降低。与这些观察结果一致，FOXK 2的过表达抑制ERα的转录活性，降低ERα靶基因的转录，并抑制ERα阳性乳腺癌细胞的增殖。相反，在MCF-7细胞中敲低FOXK 2促进细胞增殖。然而，当ERα也被敲低时，FOXK 2的敲低对细胞增殖没有影响。提示FOXK 2可能是ERα的负调控因子，它与ERα和BRCA 1/BARD 1的结合可下调ERα的转录活性，从而有效地调节ERα的功能。
Estrogen receptors (ERs) are critical regulators of breast cancer development. Identification of molecules that regulate the function of ERs may facilitate the development of more effective breast cancer treatment strategies. In this study, we showed that the forkhead transcription factor FOXK2 interacted with ERα, and inhibited ERα-regulated transcriptional activities by enhancing the ubiquitin-mediated degradation of ERα. This process involved the interaction between FOXK2 and BRCA1/BARD1, the E3 ubiquitin ligase of ERα. FOXK2 interacted with BARD1 and acted as a scaffold protein for BRCA1/BARD1 and ERα, leading to enhanced degradation of ERα, which eventually accounted for its decreased transcriptional activity. Consistent with these observations, overexpression of FOXK2 inhibited the transcriptional activity of ERα, decreased the transcription of ERα target genes, and suppressed the proliferation of ERα-positive breast cancer cells. In contract, knockdown of FOXK2 in MCF-7 cells promoted cell proliferation. However, when ERα was also knocked down, knockdown of FOXK2 had no effect on cell proliferation. These findings suggested that FOXK2 might act as a negative regulator of ERα, and its association with both ERα and BRCA1/BARD1 could lead to the down-regulation of ERα transcriptional activity, effectively regulating the function of ERα.
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DOI：
10.1093/jnci/djn309
发表时间：
2008-10-01
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Ellis MJ;Tao Y;Luo J;A'Hern R;Evans DB;Bhatnagar AS;Chaudri Ross HA;von Kameke A;Miller WR;Smith I;Eiermann W;Dowsett M
通讯作者：
Dowsett M
DOI：
10.1186/bcr2562
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kim SH;Kang HJ;Na H;Lee MO
通讯作者：
Lee MO
影响因子：
2.7
作者：
Fujii, Yoshito;Nakamura, Michio
通讯作者：
Nakamura, Michio
影响因子：
--
作者：
Fan, MY;Park, A;Nephew, KP
通讯作者：
Nephew, KP
影响因子：
3.5
作者：
Kim, Kyounghyun;Burghardt, Robert;Safe, Stephen
通讯作者：
Safe, Stephen