Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a.
Progesterone downregulation of miR-141 contributes to expansion of stem-like breast cancer cells through maintenance of progesterone receptor and Stat5a.
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孕激素（P4）已成为调节乳腺干细胞群的重要激素。在乳腺癌中，P4和合成类似物增加了管腔雌激素受体（ER）和孕酮受体（PR）阳性乳腺癌中干细胞样细胞的数量。这些细胞获得去分化细胞标志物CD 44和细胞角蛋白5（CK 5）的表达，失去管腔标志物ER和PR，并且更具治疗抗性。我们先前描述了microRNA（miR）-29a的P4下调有助于CD 44 high和CK 5+细胞的扩增。在这里，我们研究了P4下调miR-141，一个miR-200家族的肿瘤抑制因子，促进干细胞样乳腺癌细胞的增加。miR-141是miR-200家族中唯一在成熟miRNA水平下调的成员。单独稳定抑制miR-141可增加CD 44 high细胞群，并增强P4介导的CD 44 high和CK 5+细胞增加。miR-141的缺失增强了乳腺球的形成和肿瘤的发生。miR-141直接靶向PR和Stat 5a，这两种转录因子对乳腺干细胞扩增很重要。miR-141消耗增加PR蛋白水平，即使在PR表达是雌激素依赖性的细胞系中。通过siRNA或小分子抑制剂抑制Stat 5a可降低CK 5+和CD 44 high细胞中P4依赖性的增加。这些数据支持P4触发的miR-141丢失通过PR和Stat 5a（两种对控制乳腺细胞命运重要的转录因子）的失调促进乳腺癌细胞去分化的机制。
Progesterone (P4) has emerged as an important hormone regulating mammary stem cell populations. In breast cancer, P4 and synthetic analogs increase the number of stem-like cells within luminal estrogen receptor (ER) and progesterone receptor (PR) positive breast cancers. These cells gain expression of de-differentiated cell markers CD44 and cytokeratin 5 (CK5), lose luminal markers ER and PR, and are more therapy resistant. We previously described that P4-downregulation of microRNA (miR)-29a contributes to the expansion of CD44high and CK5+ cells. Here we investigated P4-downregulation of miR-141, a member of the miR-200 family of tumor suppressors, in facilitating an increase in stem-like breast cancer cells. miR-141 was the sole member of the miR-200 family P4-downregulated at the mature miRNA level in luminal breast cancer cell lines. Stable inhibition of miR-141 alone increased the CD44high population, and potentiated P4-mediated increases in both CD44high and CK5+ cells. Loss of miR-141 enhanced both mammosphere formation and tumor initiation. miR-141 directly targeted both PR and Stat5a, transcription factors important for mammary stem cell expansion. miR-141 depletion increased PR protein levels, even in cells lines where PR expression is estrogen-dependent. Stat5a suppression via siRNA or a small molecule inhibitor reduced the P4-dependent increase in CK5+ and CD44high cells. These data support a mechanism by which P4-triggered loss of miR-141 facilitates breast cancer cell de-differentiation through deregulation of PR and Stat5a, two transcription factors important for controlling mammary cell fate.
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影响因子：
64.5
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Hatziapostolou M;Polytarchou C;Aggelidou E;Drakaki A;Poultsides GA;Jaeger SA;Ogata H;Karin M;Struhl K;Hadzopoulou-Cladaras M;Iliopoulos D
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