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PNAS:恢复乳腺癌药物敏感性

2017-10-11

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导读:一种新技术可以让特定类型的乳腺癌对内分泌疗法重新敏感,它可能为难治癌症患者提供治疗。

一种新技术可以让特定类型的乳腺癌对内分泌疗法重新敏感,它可能为难治癌症患者提供治疗。至多1/3的乳腺癌不表达雌激素受体,这让它们对广泛使用的他莫昔芬等内分泌药物不敏感。

Caroline Ford及其同事发现了一种恢复雌激素受体的方法,因此也就恢复了药物敏感性。内分泌受体(ER[alpha])是他莫昔芬的入口;缺少了这种受体,这种药物就无法固定,也就让它失去了效果。此前的研究表明失去ER[alpha]与失去另一种蛋白质Wnt-5a有关,后者参与了信号传导。然而,这组作者提出,Wnt-5a信号传导可以恢复ER[alpha]在失去雌激素受体的乳腺癌细胞中的表达。他们使用人类乳腺癌细胞系确定了加入Wnt-5a或实验室开发的类似分子Foxy-5是否可以恢复ER[alpha]。这两种分子都可以恢复乳腺癌细胞系的受体表达。当这组科学家然后用他莫昔芬治疗这些细胞的时候,这些细胞对该药物敏感。

这组作者得出结论说,Foxy-5小分子可能为当前无法治疗的乳腺癌提供治疗选项。(生物谷Bioon.com)

生物谷推荐原始出处:

PNAS February 23, 2009, doi: 10.1073/pnas.0809516106

Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

Caroline E. Forda,b,1, Elin J. Ekstr?ma and Tommy Anderssona+Author Affiliations

aCell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malm? University Hospital, Malm?, 20502, Sweden; andbIntegrated Cancer Research Group, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, AustraliaEdited by Jan-?ke Gustafsson, Karolinska Institutet, Stockholm, Sweden, and approved January 8, 2009 (received for review September 23, 2008)

Abstract

One third of all breast cancers are estrogen receptor alpha (ERα) negative, carry a poor overall prognosis, and do not respond well to currently available endocrine therapies. New treatment strategies are therefore required. Loss of Wnt-5a has previously been correlated with loss of ERα in clinical breast cancer samples, and we sought to investigate this association further. Three breast cancer cell lines (MDA-MB-231, MDA-MB-468, and 4T1) lacking expression of ERα and Wnt-5a, and one breast cancer cell line (T47D) expressing both proteins were used in this study. Wnt-5a signaling was generated in ERα-negative cell lines via stimulation with either recombinant Wnt-5a protein or a Wnt-5a-derived hexapeptide (Foxy-5) possessing Wnt-5a signaling properties. ERα expression was restored at both mRNA and protein level, after treatment with recombinant Wnt-5a or Foxy-5. This restoration of expression occurred in parallel with a reduction in methylation of the ERα promoter. Up-regulated ERα could be activated, initiate transcription of progesterone receptor and pS2, and activate an estrogen response element reporter construct. Significantly, breast cancer cells re-expressing ERα responded to treatment with the selective estrogen receptor modulator tamoxifen, as measured by induction of apoptosis and cell growth inhibition. Finally, Foxy-5 also increased ERα expression in an in vivo model of ERα-negative breast cancer. This represents the first evidence that Wnt-5a signaling acts to re-establish ERα expression in ERα-negative breast cancer cells. Our data suggest that combinatorial therapy with Foxy-5 and tamoxifen should be considered as a future treatment possibility for ERα-negative breast cancer patients.

[关键词: 乳腺癌 药物 敏感性 ]

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