Open AccessPalbociclib enhances activin‐ SMAD ‐induced cytostasis in estrogen receptor‐positive breast cancer
Author(s) -
Harada Mayumi,
Morikawa Masato,
Ozawa Takayuki,
Kobayashi Mai,
Tamura Yusuke,
Takahashi Kei,
Tanabe Masahiko,
Tada Keiichiro,
Seto Yasuyuki,
Miyazono Kohei,
Koinuma Daizo
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13841
Subject(s) - smad , cyclin dependent kinase , cancer research , palbociclib , retinoblastoma protein , cdk inhibitor , estrogen receptor , phosphorylation , biology , breast cancer , cell cycle , cancer , microbiology and biotechnology , medicine , metastatic breast cancer
Cyclin‐dependent kinase ( CDK ) 4 and CDK 6 inhibitors are effective therapeutic options for hormone receptor ( HR )‐positive, human epidermal growth factor receptor 2 ( HER 2)‐negative advanced breast cancer. Although CDK 4/6 inhibitors mainly target the cyclin D‐ CDK 4/6‐retinoblastoma tumor suppressor protein ( RB ) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK 4/6 target proteins. Here, we focused on other CDK 4/6 targets, SMAD proteins. We showed that a CDK 4/6 inhibitor palbociclib and activin‐ SMAD 2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD 2 binding to the genome by inhibiting CDK 4/6‐mediated linker phosphorylation of the SMAD 2 protein. We also showed that cyclin G2 plays essential roles in SMAD 2‐dependent cytostatic response. Moreover, comparison of the SMAD 2 Ch IP ‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD 2‐mediated functions based on cell type, and enhanced SMAD 2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐ SMAD 2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer.