Miao Jiangyong, Wang Zuncai, Provencher Heather, Muir Beth, Dahiya Sonika, Carney Erin, Leong Chee-Onn, Sgroi Dennis C, Orsulic Sandra
Molecular Pathology Research Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17093-8. doi: 10.1073/pnas.0707938104. Epub 2007 Oct 17.
Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53(-/-) mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer.
在接受他莫昔芬单一疗法治疗的一部分雌激素受体阳性乳腺癌患者中,HOXB13表达失调与侵袭性临床病程及不良预后相关。由于卵巢是另一个激素反应性器官,我们研究了HOXB13是否在卵巢癌进展中发挥作用。我们发现HOXB13在多种人卵巢癌细胞系和肿瘤中表达,并且在人卵巢癌细胞系中通过RNA干扰敲低内源性HOXB13与细胞增殖减少相关。HOXB13的异位表达能够转化p53基因敲除的小鼠胚胎成纤维细胞,并促进含有p53、myc和ras基因改变的小鼠卵巢癌细胞系中的细胞增殖和不依赖贴壁的生长。在这种基因定义的卵巢癌细胞系模型中,我们证明HOXB13与激活的ras协同作用,在体内显著促进肿瘤生长,并且HOXB13赋予对他莫昔芬介导的细胞凋亡的抗性。综上所述,我们的结果支持HOXB13在卵巢癌中具有促增殖和促生存作用。