title: DMP1β, 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 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 expression. RNA-seq analyses of a publicly available database showed significantly increased DMP1β mRNA in 43-55% of human breast cancers, dependent on histological subtypes. Similarly, DMP1β protein was found to be overexpressed in ∼60% of tumours relative to their surrounding normal tissue. Importantly, alteration of DMP1 splicing and DMP1β overexpression were associated with poor clinical outcomes of the breast cancer patients, indicating that DMP1β may have a biological function. Indeed, DMP1β increased proliferation of non-tumourigenic mammary epithelial cells and knockdown of endogenous DMP1 inhibited breast cancer cell growth. To determine DMP1β's role in vivo, we established MMTV-DMP1β transgenic mouse lines. DMP1β 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 DMP1β isoform.
authors.affiliation: 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.
authors.forename: Dejan
authors.initials: D
authors.lastname: Maglic
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stovall
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fry
authors.forename: Ali
authors.initials: A
authors.lastname: Mallakin
authors.forename: Pankaj
authors.initials: P
authors.lastname: Taneja
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Kazushi
authors.initials: K
authors.lastname: Inoue
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C513309:DMP1 protein, human; C102116:Dmtf1 protein, mouse; D016326:Extracellular Matrix Proteins; D010750:Phosphoproteins; D014157:Transcription Factors
keywords: Arf; DMP1 (DMP1α and DMP1β); DMTF1; MMTV; alternative splicing; breast cancer; p53