title: Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells.
abstract: Ionizing radiation and cumulative exposure to steroid hormones are known risk factors for breast cancer. There is increasing evidence that breast tumors are driven by a subpopulation of tumor-initiating cancer stem cells (CSCs). In MCF10A non-cancerous basal-like PR(-) cells, progesterone treatment and X-rays generated ALDH(+) and CD44(+)/CD24(-) CSCs. Here, we report that in irradiated MCF10A cells, progesterone activated the PI3K/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the PI3K/Akt pathway counteracted the generation of CSCs by progesterone and irradiation. The stimulation of PI3K/Akt via mPR resulted 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. This study provides a new mechanistic basis for progesterone and radiation-induced breast cancer risk in basal cells. In addition, the elucidation of new pathways and miRNA regulations involved in CSC generation and maintenance may open the door to potential novel anti-CSC strategies.
authors.affiliation: Research Center for Radiation Protection, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan. Electronic address: vares@nirs.go.jp.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vares
authors.affiliation: Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Sai
authors.affiliation: Research Center for Radiation Protection, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Research Center for Radiation Protection, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Fujimori
authors.affiliation: Research Center for Radiation Protection, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Nenoi
authors.affiliation: Research Center for Radiation Protection, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D035683:MicroRNAs / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011374:Progesterone; D051057:Proto-Oncogene Proteins c-akt; D011980:Receptors, Progesterone; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C000715467:KLF4 protein, human; C532045:MIRN29a microRNA, human; C000604407:SNAI1 protein, human
keywords: Basal breast cancer; Cancer stem cells; Membrane progesterone receptor; Progesterone; Radiation; miRNA