The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1

被引:184
作者
Coletta, RD
Christensen, K
Reichenberger, KJ
Lamb, J
Micomonaco, D
Huang, LL
Wolf, DM
Müller-Tidow, C
Golub, TR
Kawakami, K
Ford, HL [9 ]
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Mol Genet & Biochem, Denver, CO 80262 USA
[2] Univ Estadual Campinas, Sch Dent, Discipline Pathol, BR-13414018 Piracicaba, SP, Brazil
[3] MIT, Howard Hughes Med Inst, Ctr Genome Res, Cambridge, MA 02139 USA
[4] MIT, Whitehead Inst, Ctr Genome Res, Cambridge, MA 02139 USA
[5] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[6] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Boston, MA 02115 USA
[8] Univ Munster, Dept Med A Hematol & Oncol, D-48129 Munster, Germany
[9] Univ Colorado, Hlth Sci Ctr, Dept Obstet & Gynecol, Denver, CO 80262 USA
关键词
D O I
10.1073/pnas.0401139101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Homeobox genes constitute a large family of transcription factors that are essential during normal development and are often dysregulated in cancer. However, the molecular mechanisms by which homeobox genes influence cancer remain largely unknown. Here we show that the tissue-restricted cyclin A1 is a transcriptional target of the Six1 homeoprotein. Both genes are expressed in the embryonic but not the terminally differentiated mammary gland, and Six1-knockout mice show a dramatic reduction of cyclin A1 in the embryonic mammary gland. In addition, both genes are reexpressed in breast cancers. Six1 overexpression increases cyclin Al mRNA levels and activity, cell proliferation, and tumor volume, whereas Six1 down-regulation decreases cyclin A1 mRNA levels and proliferation. Overexpression of Six1 in wild-type mouse embryonic fibroblasts, but not in knockout variants lacking the cyclin A1 gene, induces cell proliferation. Furthermore, inhibition of cyclin A1 in Six1-overexpressing mammary carcinoma cells decreases proliferation. Together these results demonstrate that cyclin A1 is required for the proliferative effect of Six1. We conclude that Six1 overexpression reinstates an embryonic pathway of proliferation in breast cancer by up-regulating cyclin A1.
引用
收藏
页码:6478 / 6483
页数:6
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