O papel protetivo da regucalcina na carcinogénese da glândula mamária

Estudos prévios do grupo de investigação liderado pela Professora Sílvia Socorro, haviam demonstrado que a regucalcina (RGN), uma proteína reguladora dos níveis de cálcio intracelular e envolvida em diversas vias de sinalização, apresenta uma expressão diminuída em casos de cancro da mama relativamente a tecidos não neoplásticos. No estudo recentemente publicado na revista Experimental Cell Research os mesmos investigadores do Centro de Investigação em Ciências da Saúde da Universidade da Beira Interior (CICS-UBI) identificaram a RGN como uma molécula com uma ação protetora na carcinogénese da glândula mamária. Ratos transgénicos com sobrexpressão da RGN apresentaram uma marcada resistência ao desenvolvimento de tumores mamários induzidos farmacologicamente, e um número significativamente mais reduzido de tumores do tipo invasivo, comparativamente aos animais controlo. Estas diferenças entre animais transgénicos e controlos parecem estar associadas aos efeitos da RGN na supressão da proliferação celular e regulação da apoptose nas células da mama. Foi ainda demonstrado que a progressão do carcinoma ductal invasivo da mama é acompanhada pela diminuição dos níveis da RGN.

Autores e Afiliações:

Ricardo Marques^a, Cátia V. Vaza, Cláudio J. Maia^a, Madalena Gomes^b, Adelina Gama^c, Gilberto Alves^a, Cecília R. Santos^a, Fernando Schmitt^b,d,e,f, Sílvia Socorro^a

^a CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

^b IPATIMUP – Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal

^c Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD), Portugal

^d Medical Faculty, University of Porto, Porto, Portugal

^e Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada

^f Department of Pathology, University Health Network, Toronto, Canada

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.

Revista: Experimental Cell Research

Link: http://www.sciencedirect.com/science/article/pii/S0014482714003358