title: Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis.
abstract: Regucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland.
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Marques
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: Cátia V
authors.initials: CV
authors.lastname: Vaz
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: Cláudio J
authors.initials: CJ
authors.lastname: Maia
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Madalena
authors.initials: M
authors.lastname: Gomes
authors.affiliation: Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Portugal.
authors.forename: Adelina
authors.initials: A
authors.lastname: Gama
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Alves
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
authors.forename: Cecília R
authors.initials: CR
authors.lastname: Santos
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Medical Faculty, University of Porto, Porto, Portugal; Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada; Department of Pathology, University Health Network, Toronto, Canada.
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
authors.affiliation: CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal. Electronic address: ssocorro@fcsaude.ubi.pt.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Socorro
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D002273:Carcinogens / Q000494:pharmacology; D053148:Caspase 3 / Q000096:biosynthesis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D019394:Ki-67 Antigen / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000473:pathology*; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
chemical_list: D002135:Calcium-Binding Proteins; D002273:Carcinogens; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; C513323:RGN protein, human; D015127:9,10-Dimethyl-1,2-benzanthracene; D053148:Caspase 3
keywords: Apoptosis; Breast cancer; Carcinogen; DMBA; Mammary gland; Regucalcin