Oncotarget

Research Papers:

Pit-1 inhibits BRCA1 and sensitizes human breast tumors to cisplatin and vitamin D treatment

Samuel Seoane _, Efigenia Arias, Rita Sigueiro, Juan Sendon-Lago, Anxo Martinez-Ordoñez, Esteban Castelao, Noemí Eiró, Tomás Garcia-Caballero, Manuel Macia, Rafael Lopez-Lopez, Miguel Maestro, Francisco Vizoso, Antonio Mouriño and Roman Perez-Fernandez

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Oncotarget. 2015; 6:14456-14471. https://doi.org/10.18632/oncotarget.3894

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Abstract

Samuel Seoane1,2, Efigenia Arias2,3, Rita Sigueiro4, Juan Sendon-Lago1,2, Anxo Martinez-Ordoñez1,2, Esteban Castelao5, Noemí Eiró6, Tomás Garcia-Caballero7, Manuel Macia3, Rafael Lopez-Lopez8, Miguel Maestro4, Francisco Vizoso6, Antonio Mouriño4, Roman Perez-Fernandez1,2

1Department of Physiology, University of Santiago de Compostela, Santiago de Compostela 15782, Spain

2Center for Research in Molecular Medicine and Chronic Diseases-CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain

3Department of Obstetrics and Gynecology, University of Santiago de Compostela, Santiago de Compostela 15782, Spain

4Department Organic Chemistry, Research Laboratory Ignacio Rivas, University of Santiago de Compostela, Santiago de Compostela 15782, Spain

5Oncology and Genetics Unit, Biomedical Research Institute of Vigo (IBIV), Complejo Hospitalario Universitario de Vigo, Servicio Galego de Saude (SERGAS), Vigo 36036, Spain

6Research Unit, Fundación Hospital de Jove, Gijón 33290, Spain

7Department of Morphological Sciences, University of Santiago de Compostela, Santiago de Compostela 15782, Spain

8Department of Clinical Oncology, University of Santiago de Compostela, Santiago de Compostela 15782, Spain

Correspondence to:

Samuel Seoane, e-mail: [email protected]

Roman Perez-Fernandez, e-mail: [email protected]

Keywords: breast cancer, Pit-1, BRCA1, cisplatin, vitamin D

Received: February 09, 2015     Accepted: April 25, 2015     Published: May 08, 2015

ABSTRACT

The POU class 1 homeobox 1 (POU1F1, also known as Pit-1), pertaining to the Pit-Oct-Unc (POU) family of transcription factors, has been related to tumor growth and metastasis in breast. However, its role in response to breast cancer therapy is unknown.

We found that Pit-1 down-regulated DNA-damage and repair genes, and specifically inhibited BRCA1 gene expression, sensitizing breast cancer cells to DNA-damage agents. Administration of 1α, 25-dihydroxy-3-epi-vitamin D3 (3-Epi, an endogenous low calcemic vitamin D metabolite) reduced Pit-1 expression, and synergized with cisplatin, thus, decreasing cell proliferation and apoptosis in vitro, and reducing tumor growth in vivo. In addition, fifteen primary cultures of human breast tumors showed significantly decreased proliferation when treated with 3-Epi+cisplatin, compared to cisplatin alone. This response positively correlated with Pit-1 levels.

Our findings demonstrate that high levels of Pit-1 and reduced BRCA1 levels increase breast cancer cell susceptibility to 3-Epi+cisplatin therapy.


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