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

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 approximate to 30% of breast cancer cases with relatively decreased DMP1 and increased DMP1 expression. RNA-seq analyses of a publicly available database showed significantly increased DMP1mRNA in 43-55% of human breast cancers, dependent on histological subtypes. Similarly, DMP1 protein was found to be overexpressed in approximate to 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. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.