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Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor prot...

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Autores principales: Harada, Mayumi, Morikawa, Masato, Ozawa, Takayuki, Kobayashi, Mai, Tamura, Yusuke, Takahashi, Kei, Tanabe, Masahiko, Tada, Keiichiro, Seto, Yasuyuki, Miyazono, Kohei, Koinuma, Daizo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317929/
https://www.ncbi.nlm.nih.gov/pubmed/30343527
http://dx.doi.org/10.1111/cas.13841
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author Harada, Mayumi
Morikawa, Masato
Ozawa, Takayuki
Kobayashi, Mai
Tamura, Yusuke
Takahashi, Kei
Tanabe, Masahiko
Tada, Keiichiro
Seto, Yasuyuki
Miyazono, Kohei
Koinuma, Daizo
author_facet Harada, Mayumi
Morikawa, Masato
Ozawa, Takayuki
Kobayashi, Mai
Tamura, Yusuke
Takahashi, Kei
Tanabe, Masahiko
Tada, Keiichiro
Seto, Yasuyuki
Miyazono, Kohei
Koinuma, Daizo
author_sort Harada, Mayumi
collection PubMed
description Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer.
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spelling pubmed-63179292019-01-08 Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer Harada, Mayumi Morikawa, Masato Ozawa, Takayuki Kobayashi, Mai Tamura, Yusuke Takahashi, Kei Tanabe, Masahiko Tada, Keiichiro Seto, Yasuyuki Miyazono, Kohei Koinuma, Daizo Cancer Sci Original Articles Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer. John Wiley and Sons Inc. 2018-11-16 2019-01 /pmc/articles/PMC6317929/ /pubmed/30343527 http://dx.doi.org/10.1111/cas.13841 Text en © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Harada, Mayumi
Morikawa, Masato
Ozawa, Takayuki
Kobayashi, Mai
Tamura, Yusuke
Takahashi, Kei
Tanabe, Masahiko
Tada, Keiichiro
Seto, Yasuyuki
Miyazono, Kohei
Koinuma, Daizo
Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
title Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
title_full Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
title_fullStr Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
title_full_unstemmed Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
title_short Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer
title_sort palbociclib enhances activin‐smad‐induced cytostasis in estrogen receptor‐positive breast cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317929/
https://www.ncbi.nlm.nih.gov/pubmed/30343527
http://dx.doi.org/10.1111/cas.13841
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