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DMP1ß, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer.
Maglic, Dejan; Stovall, Daniel B; Cline, J Mark; Fry, Elizabeth A; Mallakin, Ali; Taneja, Pankaj; Caudell, David L; Willingham, Mark C; Sui, Guangchao; Inoue, Kazushi.
Afiliação
  • Maglic D; Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA; Department of Pathology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA; Graduate Program in Molecular Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
J Pathol ; 236(1): 90-102, 2015 May.
Article em En | MEDLINE | ID: mdl-25537728
Our recent work has indicated that the DMP1 locus on 7q21, encoding a haplo-insufficient tumour suppressor, is hemizygously deleted at a high frequency in breast cancer. The locus encodes DMP1α protein, an activator of the p53 pathway leading to cell cycle arrest and senescence, and two other functionally undefined isoforms, DMP1ß and DMP1γ. In this study, we show that the DMP1 locus is alternatively spliced in ∼30% of breast cancer cases with relatively decreased DMP1α and increased DMP1ß expression. RNA-seq analyses of a publicly available database showed significantly increased DMP1ß mRNA in 43-55% of human breast cancers, dependent on histological subtypes. Similarly, DMP1ß protein was found to be overexpressed in ∼60% of tumours relative to their surrounding normal tissue. Importantly, alteration of DMP1 splicing and DMP1ß overexpression were associated with poor clinical outcomes of the breast cancer patients, indicating that DMP1ß may have a biological function. Indeed, DMP1ß increased proliferation of non-tumourigenic mammary epithelial cells and knockdown of endogenous DMP1 inhibited breast cancer cell growth. To determine DMP1ß's role in vivo, we established MMTV-DMP1ß transgenic mouse lines. DMP1ß overexpression was sufficient to induce mammary gland hyperplasia and multifocal tumour lesions in mice at 7-18 months of age. The tumours formed were adenosquamous carcinomas with evidence of transdifferentiation and keratinized deposits. Overall, we identify alternative splicing as a mechanism utilized by cancer cells to modulate the DMP1 locus through diminishing DMP1α tumour suppressor expression, while simultaneously up-regulating the tumour-promoting DMP1ß isoform.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Fatores de Transcrição / Neoplasias da Mama / Transformação Celular Neoplásica / Proteínas da Matriz Extracelular / Proliferação de Células Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Fatores de Transcrição / Neoplasias da Mama / Transformação Celular Neoplásica / Proteínas da Matriz Extracelular / Proliferação de Células Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article