Modulation of breast radiation responses by steroid hormones through its action on cancer stem cells

2015 Fiscal Year Final Research Report

• Project/Area Number: 24710066
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: National Institute of Radiological Sciences
• Principal Investigator: Vares Guillaume 国立研究開発法人放射線医学総合研究所, 放射線防護研究 センター, 研究員 (10415432)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Keywords: cancer stem cell / breast cancer / radiation / progesterone / steroid hormone / microRNA

Outline of Final Research Achievements

Progesterone (Pg) stimulated cancer stem cell expansion both in progesterone receptor (PR)-positive breast cancer cells and in PR-negative normal cells. In MCF10A basal-like PR-negative cells, Pg treatment and irradiation triggered cancer and stemness-associated microRNA regulations (such as the downregulation of miR-22 and miR-29c), which resulted in increased proportions of radiation-resistant CSCs. Pg activated the PI3k/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the PI3k/Akt pathway counteracted the generation of CSCs by Pg 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.

Free Research Field

Cancer Research, Radiation Research