2021 Fiscal Year Final Research Report

Elucidation of molecular mechanisms of the dormant switch and malignant transformation in refractory breast cancer using 3D culture.

Research Project

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Project/Area Number	19K07635
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 50010:Tumor biology-related
Research Institution	Chiba University
Principal Investigator	Nakayama Akitoshi 千葉大学, 大学院医学研究院, 特任助教 (10835226)
Co-Investigator(Kenkyū-buntansha)	田中知明千葉大学, 大学院医学研究院, 教授 (50447299) 山形一行千葉大学, 大学院医学研究院, 助教 (60455912) 永野秀和千葉大学, 大学院医学研究院, 特任講師 (60788876)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	乳癌 / p53 / 癌抑制遺伝子 / 休眠
Outline of Final Research Achievements	The gain of function caused by mutant p53 is known to be involved in cancer growth and malignant transformation. In this study, we found in 3D culture that the target gene of mutant p53 induces activation of SREBP2, a key factor in the Mevalonate pathway, as the molecular substrate for malignant phenotype acquisitions, and is involved in cancer malignancy via the isoprenoid GGPP. Moreover, Single Cell analysis was performed to clarify the downstream signals in the gain of malignant phenotypes. The results showed that a pathway in the filopodia regulatory mechanism plays important roles in the acquisition of malignant phenotypes.
Free Research Field	腫瘍生物学関連
Academic Significance and Societal Importance of the Research Achievements	乳がんは早期発見・治療により予後が良好なことが特徴であるが、一方で治療抵抗性、多臓器転移を起こす難治性乳がんは予後が悪く、乳がん治療における大きな課題である。本研究により、難治性乳がんにおける悪性化の機序の一つとして変異p53が標的遺伝子を介してメバロン酸合成経路を活性化し悪性化を導くことが明らかとなった。今後、これらの知見を創薬基盤へと発展させることで、難治性乳がんにおける悪性化形質獲得を標的とした新たな治療法や創薬の開発が期待できる。