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Establishment of Novel Anti-Hormone Therapy of Breast Cancer based on the Inhibition of Uptake Transporter of Conjugated Estrogen by Cancer Cells.

基于抑制癌细胞摄取结合雌激素转运蛋白建立新型乳腺癌抗激素疗法。

基本信息

批准号：
17390046
负责人：
TAMAI Ikumi
金额：
$ 9.47万
依托单位：
TOKYO UNIVERSITY OF SCIENCE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

More than half of breast cancer cells exhibit estrogen-dependent growth and the estrogen receptor antagonists and aromatase inhibitors are currently used for the endocrine treatment. However, after menopausal, blood concentration of estrogens such as estradiol decreases significantly and sulfate-conjugated metabolite of estrogen, estrone-3-sulfate (E3S), becomes major estrogen precursor. So, it is possible that E3S is taken up by the cells, desulfated enzymatically, and exhibits estrone receptor activity as estrogen to facilitate the proliferation of the cells. However, E3S hardly crosses the cell membrane by passive diffusion due to hydrophilic nature and requires the transporter to be taken up by the cells. Accordingly, reducing the uptake of E3S by the breast cancer cells is expected to be effective to retard the growth of breast cancer. Uptake of radio-labeled E3S by MCF7 cells was saturable and was reduced by several anionic compounds such as BSP. In addition, E3S-dependent estrogen-receptor activity was suppressed in the presence of BSP. Furthermore, a growth of MCF7 cells was increased by E3S and the growth was reduced by the addition of BSP. These results demonstrated that E3S affects the estrogen-dependent growth of breast cancer cells and the transporter for E3S expressed in the estrogen-dependent breast cancer cells should be a novel target for the endocrine treatment of the breast cancers.

超过一半的乳腺癌细胞表现出雌激素依赖性生长，雌激素受体拮抗剂和芳香酶抑制剂目前用于内分泌治疗。然而，绝经后，雌激素（例如雌二醇）的血液浓度显着降低，雌激素的硫酸盐结合代谢物雌酮-3-硫酸酯（E3S）成为主要的雌激素前体。因此，E3S可能被细胞摄取，通过酶促脱硫，并表现出雌激素受体活性，以促进细胞增殖。然而，由于E3S的亲水性，它很难通过被动扩散穿过细胞膜，并且需要转运蛋白被细胞摄取。因此，减少乳腺癌细胞对E3S的摄取有望有效延缓乳腺癌的生长。 MCF7 细胞对放射性标记 E3S 的摄取是饱和的，并且会被 BSP 等几种阴离子化合物减少。此外，BSP 存在时，E3S 依赖性雌激素受体活性受到抑制。此外，E3S增加了MCF7细胞的生长，而添加BSP则减少了生长。这些结果表明E3S影响乳腺癌细胞的雌激素依赖性生长，雌激素依赖性乳腺癌细胞中表达的E3S转运蛋白应成为乳腺癌内分泌治疗的新靶点。