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

2015; Impact Journals LLC; Volume: 6; Issue: 16 Linguagem: Inglês

10.18632/oncotarget.3894

1949-2553

Samuel Seoane, Efigenia Arias, Rita Sigüeiro, Juan Sendón-Lago, Anxo Martínez-Ordóñez, Esteban Castelao, Noemí Eiró, Tomás García‐Caballero, Manuel Macı́a, Rafael López‐López, M.A. Maestro, Francisco J. Vizoso, Antonio Mouriño, Román Pérez-Fernández,

Cancer Cells and Metastasis

// Samuel Seoane 1, 2 , Efigenia Arias 2, 3 , Rita Sigueiro 4 , Juan Sendon-Lago 1, 2 , Anxo Martinez-Ordoñez 1, 2 , Esteban Castelao 5 , Noemí Eiró 6 , Tomás Garcia-Caballero 7 , Manuel Macia 3 , Rafael Lopez-Lopez 8 , Miguel Maestro 4 , Francisco Vizoso 6 , Antonio Mouriño 4 , Roman Perez-Fernandez 1, 2 1 Department of Physiology, University of Santiago de Compostela, Santiago de Compostela 15782, Spain 2 Center for Research in Molecular Medicine and Chronic Diseases-CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain 3 Department of Obstetrics and Gynecology, University of Santiago de Compostela, Santiago de Compostela 15782, Spain 4 Department Organic Chemistry, Research Laboratory Ignacio Rivas, University of Santiago de Compostela, Santiago de Compostela 15782, Spain 5 Oncology and Genetics Unit, Biomedical Research Institute of Vigo (IBIV), Complejo Hospitalario Universitario de Vigo, Servicio Galego de Saude (SERGAS), Vigo 36036, Spain 6 Research Unit, Fundación Hospital de Jove, Gijón 33290, Spain 7 Department of Morphological Sciences, University of Santiago de Compostela, Santiago de Compostela 15782, Spain 8 Department of Clinical Oncology, University of Santiago de Compostela, Santiago de Compostela 15782, Spain Correspondence to: Samuel Seoane, e-mail: samuel.seoane@usc.es Roman Perez-Fernandez, e-mail: roman.perez.fernandez@usc.es 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 D 3 (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.