Progesterone Receptor B signaling Reduces Breast Cancer Cell Aggressiveness: Role of Cyclin-D1/Cdk4 Mediating Paxillin Phosphorylation
Autor: | Diego Sisci, Loredana Mauro, Francesca Giordano, Marilena Lanzino, Stefania Marsico, Francesca Ida Montalto, Sebastiano Andò, Saveria Aquila, Chiara Chiodo, Maria Luisa Panno, Francesca De Amicis |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cancer Research Progesterone receptor B Biology lcsh:RC254-282 Article Metastasis Focal adhesion 03 medical and health sciences 0302 clinical medicine Cyclin D1 Breast cancer medicine Paxillin paxillin Kinase Rho GTPase EMT luminal A Cell migration lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens invasion medicine.disease 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research |
Zdroj: | Cancers Cancers, Vol 11, Iss 8, p 1201 (2019) Volume 11 Issue 8 |
ISSN: | 2072-6694 |
Popis: | Progesterone-Receptor (PR) positivity is related with an enhanced response to breast cancer therapy, conversely cyclin D1 (CD1) is a retained marker of poor outcome. Herein, we demonstrate that hydroxyprogesterone (OHPg) through progesterone receptor B (PR-B) reduces breast cancer cell aggressiveness, by targeting the cytoplasmic CD1. Specifically, OHPg diminishes CD1 expression by a transcriptional regulation due to the recruitment of PR-B at a canonical half-PRE site of the CD1 promoter, together with HDAC1, determining a chromatin conformation less prone for gene transcription. CD1, together with its kinase partner Cdk4, regulates cell migration and metastasis, through the association with key components of focal adhesion, such as Paxillin (Pxn). Kaplan-Meier analysis shows that low Pxn expression was associated with increased distant metastasis-free survival in luminal A PR+ breast carcinomas. Interestingly, OHPg treatment reduced Pxn content in T47-D and MCF-7 cells besides, the interaction between endogenous cytoplasmic CD1/Cdk4 with Pxn was reduced. This was consistent with the reduction of p-Ser83Pxn levels, crucially causing the delay in cell migration and a concomitant inhibition of Rac1 activity and p-PAK. Collectively, these findings support the role of PR-B in breast epithelial cell integrity and reinforce the importance in targeting PR-B as a potential strategy to restrict breast tumor cell invasion and metastasis. |
Databáze: | OpenAIRE |
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