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Cell Cycle. 2017 Aug 3;16(15):1453-1464. doi: 10.1080/15384101.2017.1338988. Epub 2017 Jul 5.

Inhibition of CDK-mediated Smad3 phosphorylation reduces the Pin1-Smad3 interaction and aggressiveness of triple negative breast cancer cells.

Author information

1
a Driskill Graduate Program , Northwestern University , Chicago , IL , USA.
2
b University of Michigan , Ann Arbor , MI , USA.
3
c Department of Obstetrics and Gynecology , Northwestern University , Chicago , IL , USA.
4
d Department of Surgery , University of Michigan , Ann Arbor , MI , USA.
5
e Northwestern University Feinberg School of Medicine , Chicago , IL , USA.
6
f Department of Biomedical Engineering , University of Michigan , Ann Arbor , MI , USA.

Abstract

Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. Although TNBC is not defined by specific therapeutic targets, a subset of patients have tumors that overexpress cyclins. High cyclin D/E expression catalyzes CDK4/2 activity. In turn, CDK4/2 can non-canonically phosphorylate Smad3, a key TGFβ signaling intermediate, and this phosphorylation has been associated with the shift from tumor-suppressive to oncogenic TGFβ pathway action in breast oncogenesis. Additionally, CDK-mediated Smad3 phosphorylation facilitates an interaction between Smad3 and Pin1, a cis-trans isomerase that is also overexpressed in aggressive breast cancers. Treatment with CYC065, a CDK2/9 inhibitor, decreased non-canonical Smad3 phosphorylation and inhibited the Pin1-Smad3 interaction. We hypothesized that the interaction of Pin1 and Smad3, facilitated by CDK-mediated Smad3 phosphorylation, promotes TNBC cell aggressiveness. Inhibition of the Pin1-Smad3 interaction in TNBC cell lines, through depletion of Pin1 or CYC065 treatment, resulted in decreased cell migration/invasion and impeded the EMT program. Inhibition of CDK-mediated phosphorylation of Smad3 by mutagenesis also decreased cell migration, underscoring the importance of non-canonical CDK2 phosphorylation of Smad3 to enable cell motility. Pin1 depletion restored Smad3 protein levels and tumor-suppressive activity, suggesting that the Pin1-Smad3 interaction has a negative impact on canonical Smad3 action. Collectively, the data show that the Pin1-Smad3 interaction, facilitated by CDK-mediated Smad3 phosphorylation, is associated with oncogenic TGFβ signaling and breast cancer progression. Inhibition of this interaction with CYC065 treatment may provide an important therapeutic option for TNBC patients.

KEYWORDS:

CDK inhibitor; CDK2; CDK9; EMT; Pin1; Smad3; TGFβ; cell cycle; cyclin; invasion; migration; triple negative breast cancer

PMID:
28678584
PMCID:
PMC5553400
DOI:
10.1080/15384101.2017.1338988
[Indexed for MEDLINE]
Free PMC Article

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