Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism
Abstract Inhibitors targeting cyclin‐dependent kinases 4 and 6 (CDK4/6) to block cell cycle progression have been effective in treating hormone receptor‐positive breast cancer, but triple‐negative breast cancer (TNBC) remains largely resistant, limiting their clinical applicability. The study reveal...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413103 |
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| author | Yilan Yang Jiatao Liao Zhe Pan Jin Meng Li Zhang Wei Shi Xiaofang Wang Xiaomeng Zhang Zhirui Zhou Jurui Luo Xingxing Chen Zhaozhi Yang Xin Mei Jinli Ma Zhen Zhang Yi‐Zhou Jiang Zhi‐Min Shao Fei Xavier Chen Xiaoli Yu Xiaomao Guo |
| author_facet | Yilan Yang Jiatao Liao Zhe Pan Jin Meng Li Zhang Wei Shi Xiaofang Wang Xiaomeng Zhang Zhirui Zhou Jurui Luo Xingxing Chen Zhaozhi Yang Xin Mei Jinli Ma Zhen Zhang Yi‐Zhou Jiang Zhi‐Min Shao Fei Xavier Chen Xiaoli Yu Xiaomao Guo |
| author_sort | Yilan Yang |
| collection | DOAJ |
| description | Abstract Inhibitors targeting cyclin‐dependent kinases 4 and 6 (CDK4/6) to block cell cycle progression have been effective in treating hormone receptor‐positive breast cancer, but triple‐negative breast cancer (TNBC) remains largely resistant, limiting their clinical applicability. The study reveals that transcription regulator cyclin‐dependent kinase7 (CDK7) is a promising target to circumvent TNBC's inherent resistance to CDK4/6 inhibitors. Combining CDK4/6 and CDK7 inhibitors significantly enhances therapeutic effectiveness, leading to a marked decrease in cholesterol biosynthesis within cells. This effect is achieved through reduced activity of the transcription factor forkhead box M1 (FOXM1), which normally increases cholesterol production by inducing SREBF1 expression. Furthermore, this dual inhibition strategy attenuates the recruitment of sterol regulatory element binding transcription factor 1 (SREBP1) and p300 to genes essential for cholesterol synthesis, thus hindering tumor growth. This research is corroborated by an in‐house cohort showing lower survival rates in TNBC patients with higher cholesterol production gene activity. This suggests a new treatment approach for TNBC by simultaneously targeting CDK4/6 and CDK7, warranting additional clinical trials. |
| format | Article |
| id | doaj-art-2839a0df09634dd9aed78d4bd4e541a0 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2839a0df09634dd9aed78d4bd4e541a02025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202413103Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol MetabolismYilan Yang0Jiatao Liao1Zhe Pan2Jin Meng3Li Zhang4Wei Shi5Xiaofang Wang6Xiaomeng Zhang7Zhirui Zhou8Jurui Luo9Xingxing Chen10Zhaozhi Yang11Xin Mei12Jinli Ma13Zhen Zhang14Yi‐Zhou Jiang15Zhi‐Min Shao16Fei Xavier Chen17Xiaoli Yu18Xiaomao Guo19Department of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Oncology Shanghai Medical College Fudan University No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Renji Hospital School of Medicine Shanghai Jiao Tong University No.1630 Dongfang Road Shanghai 200127 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Oncology Shanghai Medical College Fudan University No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Oncology Shanghai Medical College Fudan University No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaDepartment of Radiation Oncology Fudan University Shanghai Cancer Center No.270 Dong'an Road Shanghai 200032 ChinaAbstract Inhibitors targeting cyclin‐dependent kinases 4 and 6 (CDK4/6) to block cell cycle progression have been effective in treating hormone receptor‐positive breast cancer, but triple‐negative breast cancer (TNBC) remains largely resistant, limiting their clinical applicability. The study reveals that transcription regulator cyclin‐dependent kinase7 (CDK7) is a promising target to circumvent TNBC's inherent resistance to CDK4/6 inhibitors. Combining CDK4/6 and CDK7 inhibitors significantly enhances therapeutic effectiveness, leading to a marked decrease in cholesterol biosynthesis within cells. This effect is achieved through reduced activity of the transcription factor forkhead box M1 (FOXM1), which normally increases cholesterol production by inducing SREBF1 expression. Furthermore, this dual inhibition strategy attenuates the recruitment of sterol regulatory element binding transcription factor 1 (SREBP1) and p300 to genes essential for cholesterol synthesis, thus hindering tumor growth. This research is corroborated by an in‐house cohort showing lower survival rates in TNBC patients with higher cholesterol production gene activity. This suggests a new treatment approach for TNBC by simultaneously targeting CDK4/6 and CDK7, warranting additional clinical trials.https://doi.org/10.1002/advs.202413103breast cancerCDK4/6CDK7cholesterol metabolism |
| spellingShingle | Yilan Yang Jiatao Liao Zhe Pan Jin Meng Li Zhang Wei Shi Xiaofang Wang Xiaomeng Zhang Zhirui Zhou Jurui Luo Xingxing Chen Zhaozhi Yang Xin Mei Jinli Ma Zhen Zhang Yi‐Zhou Jiang Zhi‐Min Shao Fei Xavier Chen Xiaoli Yu Xiaomao Guo Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism Advanced Science breast cancer CDK4/6 CDK7 cholesterol metabolism |
| title | Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism |
| title_full | Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism |
| title_fullStr | Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism |
| title_full_unstemmed | Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism |
| title_short | Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism |
| title_sort | dual inhibition of cdk4 6 and cdk7 suppresses triple negative breast cancer progression via epigenetic modulation of srebp1 regulated cholesterol metabolism |
| topic | breast cancer CDK4/6 CDK7 cholesterol metabolism |
| url | https://doi.org/10.1002/advs.202413103 |
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