Elucidation of molecular mechanism of cancer stem cell niche at the very early stage aiming at cancer prevention

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22557
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Gotoh Noriko 金沢大学, がん進展制御研究所, 教授 (10251448)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: 乳がん / 早期病変 / Ductal carcinoma in situ / 微小環境 / がん予防

Outline of Final Research Achievements

We demonstrate that FRS2β an adaptor protein expressed in a small subset of epithelial cells, triggers the pro-inflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β-deficiency in a mouse mammary tumor virus (MMTV)-ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found co-localization of FRS2β and the NEMO subunit of the IκB kinase (IKK) complex in early endosomes led to activation of nuclear factor-κB (NFκB) a master regulator of inflammation. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β-NFκB axis uncovers a hitherto unknown molecular link between the pro-inflammatory changes and the disease onset.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

現在，乳がんの早期病変Ductal carcinoma in situ (DCIS)はマンモグラフィで見つけることができる。しかし，その後増殖して悪性の浸潤がんになっていくかどうか見極めがつかないため，手術という侵襲性の高い治療法しか選択肢がなく，実臨床における問題となっている。本研究をさらに発展させることにより，乳がん発症前に整えられている乳腺微小環境を標的とする治療を行うことが可能になると考えられる。ひいては乳がんの発症予防，早期の治療が実現し，従来であれば乳がんにより命を落としていた人々が救われることが期待される。