Oncogene：靶向miRNA-29抑制乳腺癌分化

最近，研究人员发现通过抑制一个关键的microRNA抑制乳腺癌细胞获得干细胞样特性的能力，在他们还没有分化前，而一旦分化获得干细胞样特性时会更耐化疗，患者预后也较差。相关研究论文发表在Oncogene杂志上。

论文的第一作者Diana Cittelly博士表示：我们将寻找microRNAs在乳腺癌细胞分化成具有侵略性、耐化疗特性的癌细胞表型中的作用，化疗耐药表型的乳腺癌细胞分化的microRNA。因为一个microRNA可以调节许多基因参与癌症信号途径，我们希望找到一个能产生很多后续效应的靶基因。
 
具体来说，该项研究表明孕激素能调节miRNA-29，miRNA-29是一个能决定细胞基因能否翻译表达成蛋白的分子。孕激素对miRNA-29的这种调节导致了一个级联反应刺激乳腺癌细胞获到干细胞样特性。在动物模型中，这些干细胞样细胞帮助乳腺癌细胞抵抗目前的治疗手段。

Cittelly说我们可以操纵这个细胞系的miRNA-29，我们希望技术不是太远，这将使我们能够在未来递送miRNA-29进入人乳腺癌细胞中去。抑制miRNA-29的作用，乳腺癌细胞将无法获得干细胞样特性，失去他们的激素依赖特性。

编译自：The Making and Unmaking of Stem-Like, Aggressive Breast Cancer Cells

doi:10.1038/onc.2012.275
PMC:
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Progestin suppression of miR-29 potentiates dedifferentiation of breast cancer cells via KLF4

D M Cittelly, J Finlay-Schultz, E N Howe, N S Spoelstra, S D Axlund, P Hendricks, B M Jacobsen, C A Sartorius and J K Richer

The female hormone progesterone (P4) promotes the expansion of stem-like cancer cells in estrogen receptor (ER)- and progesterone receptor (PR)-positive breast tumors. The expanded tumor cells lose expression of ER and PR, express the tumor-initiating marker CD44, the progenitor marker cytokeratin 5 (CK5) and are more resistant to standard endocrine and chemotherapies. The mechanisms underlying this hormone-stimulated reprogramming have remained largely unknown. In the present study, we investigated the role of microRNAs in progestin-mediated expansion of this dedifferentiated tumor cell population. We demonstrate that P4 rapidly downregulates miR-29 family members, particularly in the CD44+ cell population. Downregulation of miR-29 members potentiates the expansion of CK5+ and CD44+ cells in response to progestins, and results in increased stem-like properties in vitro and in vivo. We demonstrate that miR-29 directly targets Krüppel-like factor 4 (KLF4), a transcription factor required for the reprogramming of differentiated cells to pluripotent stem cells, and for the maintenance of breast cancer stem cells. These results reveal a novel mechanism, whereby progestins increase the stem cell-like population in hormone-responsive breast cancers, by decreasing miR-29 to augment PR-mediated upregulation of KLF4. Elucidating the mechanisms whereby hormones mediate the expansion of stem-like cells furthers our understanding of the progression of hormone-responsive breast cancers.