Yasmeen Amber, Bismar Tarek A, Kandouz Mustapha, Foulkes William D, Desprez Pierre-Yves, Al Moustafa Ala-Eddin
Program in Cancer Genetics, Oncology Department, McGill University, Montreal, Quebec, Canada.
Cell Cycle. 2007 Aug 15;6(16):2038-42. doi: 10.4161/cc.6.16.4555. Epub 2007 Jun 6.
Human papillomaviruses (HPVs) could be important risk factors for breast carcinogenesis and metastasis, as roughly 50% of breast cancers are positive for high-risk HPVs. To determine the role of high-risk HPVs in human breast carcinogenesis and metastasis, we examined the effect of E6/E7 of HPV type 16 in two non-invasive breast cancer cell lines, MCF7 and BT20. We report that E6/E7 of HPV type 16 induces cell invasive and metastatic abilities of MCF7 and BT20 in vitro and in vivo, respectively, in comparison with the wild type cells. This is accompanied by an upregulation of Id-1, a family member of helix-loop-helix (HLH) transcription factors, in MCF7 and BT20 cell lines which express E6/E7. Earlier studies have reported that Id-1 regulates cell invasion and metastasis of human breast cancer cells. To gauge the role of Id-1 in cell invasion and metastasis induced by E6/E7 of HPV type 16, we investigated the effect of E6/E7 in mouse normal embryonic fibroblast (NEF) and knockout Id-1 (Id-1(-/-)) cells. We establish that E6/E7 induces cell invasive ability in NEF but not Id-1(-/-) cells; moreover, we were able to inhibit the invasion ability of MCF7-E6/E7 and BT20-E6/E7 using Id-1 antisense retroviruses. Furthermore, we report that E6/E7 oncoproteins up-regulate Id-1 promoter activity in MCF7 and BT20 cells. We also found that HPV type 16 is present in all invasive and metastatic breast cancer and less frequently in in-situ breast cancer as opposed to normal mammary tissue. In parallel, we demonstrate that Id-1 overexpression is correlated with the presence of HPV type 16 in human invasive and metastatic breast cancer. These data suggest that high-risk HPV infections can induce cell invasion and metastasis in breast cancer through Id-1 regulation.
人乳头瘤病毒（HPVs）可能是乳腺癌发生和转移的重要风险因素，因为大约50%的乳腺癌高危型HPVs呈阳性。为了确定高危型HPVs在人类乳腺癌发生和转移中的作用，我们检测了16型HPV的E6/E7对两种非侵袭性乳腺癌细胞系MCF7和BT20的影响。我们报告，与野生型细胞相比，16型HPV的E6/E7分别在体外和体内诱导了MCF7和BT20的细胞侵袭和转移能力。这伴随着在表达E6/E7的MCF7和BT20细胞系中，螺旋-环-螺旋（HLH）转录因子家族成员Id-1的上调。早期研究报告称，Id-1调节人类乳腺癌细胞的侵袭和转移。为了评估Id-1在16型HPV的E6/E7诱导的细胞侵袭和转移中的作用，我们研究了E6/E7对小鼠正常胚胎成纤维细胞（NEF）和Id-1基因敲除（Id-1(-/-)）细胞的影响。我们证实E6/E7在NEF中诱导细胞侵袭能力，但在Id-1(-/-)细胞中则不然；此外，我们能够使用Id-1反义逆转录病毒抑制MCF7-E6/E7和BT20-E6/E7的侵袭能力。此外，我们报告E6/E7癌蛋白上调MCF7和BT20细胞中Id-1启动子活性。我们还发现，与正常乳腺组织相比，16型HPV存在于所有侵袭性和转移性乳腺癌中，而在原位乳腺癌中出现的频率较低。同时，我们证明Id-1过表达与人类侵袭性和转移性乳腺癌中16型HPV的存在相关。这些数据表明，高危型HPV感染可通过Id-1调节诱导乳腺癌细胞侵袭和转移。
