Brake Tiffany, Lambert Paul F
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, 1400 University Avenue, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2490-5. doi: 10.1073/pnas.0409883102. Epub 2005 Feb 7.
Cervical cancer is a leading cause of death by cancer among women worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer, but other factors likely contribute to cervical cancer, because these cancers commonly arise decades after initial exposure to HPV. Estrogen is thought to be one such cofactor; however, its temporal requirements in human cervical cancer are not known. Here we evaluate the temporal requirements of estrogen in cervical carcinogenesis in a mouse model for HPV-associated cervical cancer. Tumors arising in HPV16 transgenic mice treated with estrogen for 9 months were greatly increased in their size compared with tumors developing after 6 months of estrogen treatment. HPV16 transgenic mice treated 6 months with estrogen followed by 3 months without exogenous estrogen had significantly fewer tumors and the tumors were smaller and less aggressive than those arising in mice treated the full 9 months. Importantly, cervical cancers that arose in the mice treated the first 6 of 9 months with estrogen must have regressed, based upon the reduced incidence of cancers in these mice compared with those treated for 6 months with estrogen, then immediately analyzed. We conclude that estrogen plays a critical role not only in the genesis of cervical cancer but also in its persistence and continued development in this mouse model. These findings raise the clinically relevant possibility that, if human cervical cancer has a similar dependence on estrogen for continued tumor growth, then antiestrogen therapy may be effective in the treatment of cervical cancer.
宫颈癌是全球女性癌症死亡的主要原因之一。高危型人乳头瘤病毒（HPV）是宫颈癌的主要致病因素，但其他因素可能也与宫颈癌有关，因为这些癌症通常在初次感染HPV数十年后才出现。雌激素被认为是其中一个辅助因素；然而，其在人类宫颈癌中的时间需求尚不清楚。在此，我们在HPV相关宫颈癌小鼠模型中评估雌激素在宫颈癌发生过程中的时间需求。与接受6个月雌激素治疗后形成的肿瘤相比，接受9个月雌激素治疗的HPV16转基因小鼠产生的肿瘤体积大幅增大。先接受6个月雌激素治疗，随后3个月不接受外源性雌激素治疗的HPV16转基因小鼠的肿瘤明显较少，且肿瘤体积更小，侵袭性也比接受完整9个月治疗的小鼠所产生的肿瘤更低。重要的是，与那些接受6个月雌激素治疗后立即进行分析的小鼠相比，在前9个月的前6个月接受雌激素治疗的小鼠中宫颈癌发生率降低，这表明这些小鼠体内产生的宫颈癌必定已经消退。我们得出结论，在这个小鼠模型中，雌激素不仅在宫颈癌的发生中起关键作用，而且在其持续存在和进一步发展中也起关键作用。这些发现提出了一个具有临床相关性的可能性，即如果人类宫颈癌在肿瘤持续生长方面对雌激素有类似的依赖性，那么抗雌激素疗法可能对宫颈癌治疗有效。
