シンポジウム 2

The replicative factor MCM10 maintains patientderived breast cancer stem-like cells that
constitutively experience DNA replicative stress
Breast cancer is the most common type of cancer among women throughout the world.
The increasing rate of mortality due to breast cancer raises serious problems. Recent evidence
indicates that tumor tissues are comprised of heterogeneous cell populations including a
relatively small number of cancer stem-like cells (CSCs) and large number of differentiatedcancer cells. CSCs tend to survive irrespective of conventional chemotherapy, radiotherapy, andNoriko Gotoh
Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University

1998 Human Frontier Science Program Organization (HFSPO), Long Term Fellowship1999 The Uehara Memorial Foundation, Research Fellowship2006 The NOVARTIS Foundation for the Promotion of Science, Novartis Research Grant
2007 The Naito Foundation, Research Grant
2007 The Cell Science Research Foundation, Research Grant
2018

Princess Takamatsu Cancer Research Fund, Research Grant

following treatment with molecular targeted drugs, because these treatment strategies target
rapidly proliferating differentiated cancer cells but not CSCs. Targeting CSCs is thus important
to improve the prognosis of cancer patients, however, molecular targeting drugs against CSCs
are still unmet needs, since it is still largely uncertain the molecular mechanisms how CSCs aremaintained in tumor tissues.
We uncover a critical role of the replication factor mini-chromosome maintenance protein
10 (MCM10) in enabling breast cancer-derived CSCs to deal with constitutively accumulating
DNA replicative stress. Transcriptomic analysis of patient-derived cultured breast cancer
cells revealed that MCM10 was strongly upregulated in CSC-enriched spheroid cells. Elevated
MCM10 expression was significantly correlated with worse prognosis in breast cancer patients.
Moreover, CSC-enriched spheroid cells showed high levels of DNA replicative stress, suggestingthat elevated MCM10 levels are important for CSC survival and proliferation. Consistent withthis hypothesis, MCM10 depletion decreased cell proliferation, tumorigenesis, tumor sphereforming capacity, expression levels of stemness markers, and tumor-initiating capacity of breast
cancer patient derived xenograft (PDX) model. Furthermore, we demonstrated overexpression ofMCM10 helped cells to proliferate in medium containing hydroxyurea (HU), a chemotherapeutic
agent that induces DNA damage and replicative stress. Conversely, MCM10 depletion made[References]
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S, Sato A, Nishioka K, Tsuji E, Yano M, Ogawa T, Ishii H, Mori M, Akashi K, Okamoto K, Tanabe M,Tada K, Tojo A, Gotoh N .: Semaphorin signaling via MICAL3 induces symmetric cell division to expand
breast cancer stem-like cells. Proc Natl Acad Sci, USA , 116, 625-630, 2019.
3. Nishimura T, Nakata A, Chen X, Nishi K, Meguro-Horike M, Sasaki S, Kita K, Horike S-I, Saitoh K, Kato K,Igarashi K, Murayama T, Kohno S, Takahashi C, Mukaida N, Yano S, Soga T, Tojo A, Gotoh N.: Cancer
stem-like properties and gefitinib-resistance are dependent on purine synthetic metabolism mediatedby the mitochondrial enzyme MTHFD2. Oncogene , 38, 2464-2481, 2019.
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T, Tojo A, Miyano S, Gotoh N.: Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast
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cells more sensitive to HU and mitomycin C (MMC), another inducer of replicative stress.
We therefore conclude MCM10 plays critical roles for cancer cell proliferation under DNA
replicative stress, which is more pronounced in CSCs and in cells treated with chemotherapeutic
agents, and propose to target MCM10 for therapy of both CSCs and other cancer cells.

Noriko Gotoh
Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University
1989
1993
1998
2001
2005
2007
2013

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Kanazawa University School of Medicine, MD
PhD, Assistant professor, Institute of Medical Science, The University of Tokyo
Visiting Scientist, New York University Medical Center, Dept PharmacologyInstitute of Medical Science, The University of Tokyo, Division of Genetics, Lecturer
Institute of Medical Science, The University of Tokyo, Division of Genetics,
Associate Professor
Institute of Medical Science, The University of Tokyo, Division of Systems
Biomedical Technology, Associate Professor
Cancer Research Institute, Kanazawa University, Division of Cancer Cell Biology,Professor

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