Prevention of cancer dormancy by Fbxw7 ablation eradicates disseminated tumor cells

Hideyuki Shimizu, Shoichiro Takeishi, Hirokazu Nakatsumi, Keiichi Nakayama

Research output: Contribution to journalArticle

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Abstract

Dormant cancer cells known as disseminated tumor cells (DTCs) are often present in bone marrow of breast cancer patients. These DTCs are thought to be responsible for the incurable recurrence of breast cancer. The mechanism underlying the long-term maintenance of DTCs remains unclear, however. Here, we show that Fbxw7 is essential for the maintenance of breast cancer dormancy. Genetic ablation of Fbxw7 in breast cancer cells disrupted the quiescence of DTCs, rendering them proliferative, in mouse xenograft and allograft models. Fbxw7-deficient DTCs were significantly depleted by treatment with paclitaxel, suggesting that cell proliferation induced by Fbxw7 ablation sensitized DTCs to chemotherapy. The combination of Fbxw7 ablation and chemotherapy reduced the number of DTCs even when applied after tumor cell dissemination. Mice injected with Fbxw7-deficient cancer cells survived longer after tumor resection and subsequent chemotherapy than did those injected with wild-type cells. Furthermore, database analysis revealed that breast cancer patients whose tumors expressed FBXW7 at a high level had a poorer prognosis than did those with a low FBXW7 expression level. Our results suggest that a wake-up strategy for DTCs based on Fbxw7 inhibition might be of value in combination with conventional chemotherapy for the treatment of breast cancer.

Original languageEnglish
JournalJCI insight
Volume4
Issue number4
DOIs
Publication statusPublished - Feb 21 2019

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Neoplasms
Breast Neoplasms
Drug Therapy
Paclitaxel
Heterografts
Allografts
Bone Marrow
Maintenance
Cell Proliferation
Databases
Recurrence
Therapeutics

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Prevention of cancer dormancy by Fbxw7 ablation eradicates disseminated tumor cells. / Shimizu, Hideyuki; Takeishi, Shoichiro; Nakatsumi, Hirokazu; Nakayama, Keiichi.

In: JCI insight, Vol. 4, No. 4, 21.02.2019.

Research output: Contribution to journalArticle

Shimizu, Hideyuki ; Takeishi, Shoichiro ; Nakatsumi, Hirokazu ; Nakayama, Keiichi. / Prevention of cancer dormancy by Fbxw7 ablation eradicates disseminated tumor cells. In: JCI insight. 2019 ; Vol. 4, No. 4.
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