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DMP1?, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer.

ABSTRACT: 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 DMP1? protein, an activator of the p53 pathway leading to cell cycle arrest and senescence, and two other functionally undefined isoforms, DMP1? and DMP1?. In this study, we show that the DMP1 locus is alternatively spliced in ?30% of breast cancer cases with relatively decreased DMP1? and increased DMP1? expression. RNA-seq analyses of a publicly available database showed significantly increased DMP1? mRNA in 43-55% of human breast cancers, dependent on histological subtypes. Similarly, DMP1? protein was found to be overexpressed in ?60% of tumours relative to their surrounding normal tissue. Importantly, alteration of DMP1 splicing and DMP1? overexpression were associated with poor clinical outcomes of the breast cancer patients, indicating that DMP1? may have a biological function. Indeed, DMP1? increased proliferation of non-tumourigenic mammary epithelial cells and knockdown of endogenous DMP1 inhibited breast cancer cell growth. To determine DMP1?'s role in vivo, we established MMTV-DMP1? transgenic mouse lines. DMP1? 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 DMP1? tumour suppressor expression, while simultaneously up-regulating the tumour-promoting DMP1? isoform.

SUBMITTER: Maglic D

PROVIDER: S-EPMC4398631 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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DMP1β, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer.

Maglic Dejan D Stovall Daniel B DB Cline J Mark JM Fry Elizabeth A EA Mallakin Ali A Taneja Pankaj P Caudell David L DL Willingham Mark C MC Sui Guangchao G Inoue Kazushi K

The Journal of pathology 20150209 1

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, DMP1β 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 DMP1β expre ...[more]

PMID: 25537728

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Project description:Although a small number of cardiomyocytes may reenter the cell cycle after injury, the adult mammalian heart is incapable of a robust cardiomyocyte proliferation. Periostin, a secreted extracellular matrix protein, has been implicated as a regulator of cardiomyocyte proliferation; however, this role remains controversial. Alternative splicing of the human periostin gene results in 6 isoforms lacking sequences between exons 17 and 21, in addition to full-length periostin. We previously showed that exosomes (Exo) secreted by human cardiac explant-derived progenitor cells (CPC) carried periostin. Here, we aimed to investigate their cell cycle activity. Methods: CPC were derived as the cellular outgrowth of ex vivo cultured cardiac atrial explants. Exo were purified from CPC conditioned medium using size exclusion chromatography. Exosomal periostin was analyzed by Western blotting using a pair of antibodies (one raised against aa 537-836, and one raised against amino acids mapping at exon 17 of human periostin), by ELISA, and by cryo-EM with immune-gold labeling. Cell cycle activity was assessed in neonatal rat cardiomyocytes, in human induced pluripotent stem cell (iPS)-derived cardiomyocytes, and in adult rat cardiomyocytes after myocardial infarction. The role of periostin in cell cycle activity was investigated by transfecting donor CPC with a siRNA against this protein. Results: Periostin expression in CPC-secreted exosomes was detected using the antibody raised against aa 537-836 of the human protein, but not with the exon 17-specific antibody, consistent with an isoform lacking exon 17. Periostin was visualized on vesicle surfaces by cryo-EM and immune-gold labeling. CPC-derived exosomes induced cell proliferation in neonatal rat cardiomyocytes both in vitro and in vivo, in human iPS-derived cardiomyocytes, and in adult rat cardiomyocytes after myocardial infarction. Exo promoted phosphorylation of focal adhesion kinase (FAK), actin polymerization, and nuclear translocation of Yes-associated protein (YAP) in cardiomyocytes. Knocking down of periostin or YAP, or blocking FAK phosphorylation with PF-573228 nullified Exo-induced proliferation. A truncated human periostin peptide (aa 22-669), but not recombinant human full-length periostin, mimicked the pro-proliferative activity of exosomes. Conclusions: Our results show, for the first time, that CPC-secreted exosomes promote cardiomyocyte cell cycle-reentry via a short periostin isoform expressed on their surfaces, whereas recombinant full-length periostin does not. These findings highlight isoform-specific roles of periostin in cardiomyocyte proliferation.

Dataset Information

DMP1?, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer.

Publications

DMP1β, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer.

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