Presentation Progesterone generates basal-like cancer stem cells via membrane progesterone receptor-triggered signaling

Vares, Guillaume  ,  崔, 星  ,  王, 冰  ,  藤森, 亮  ,  根井, 充  ,  中島, 徹夫

Basal-like breast cancer is of particular concern, due to its high frequency, lack of effective therapies and poor prognosis. Ionizing radiation and cumulative exposure to steroid hormones are known risk factors for breast cancer. Because of their tumor-initiating properties, cancer stem cells (CSCs) were proposed to be responsible for relapse and metastasis. In MCF10A non-cancerous basal-like PR-negative cells, progesterone (P4) treatment and 1 Gy X-rays generated ALDH+ and CD44+/CD24- CSCs. Here, we report that P4 activated the Pi3k/Akt pathway via membrane progesterone receptor (mPR), resulting in the inactivation of FOXO transcriptional activity, the upregulation of snail and slug expression and a downregulation of miR-29 expression, which led to increased levels of KLF4, a transcription factor required for breast CSC maintenance. Stabilization of miR-29 expression impeded the generation of CSCs, while its inhibition alone was sufficient to generate CSCs. The elucidation of new pathways and miRNA regulations involved in basal-like CSC maintenance may open the door to new strategies for BBC primary or adjuvant therapy, which may be effective at preventing metastasis and relapse.

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