Abstract
Our recent study shows a pivotal role of Dmp1 in quenching hyperproliferative signals from HER2 to the Arf-p53 pathway as a safety mechanism to prevent breast carcinogenesis. To directly demonstrate the role of Dmp1 in preventing HER2/neu-driven oncogenic transformation, we established Flag-Dmp1α transgenic mice (MDTG) under the control of the mouse mammary tumor virus (MMTV) promoter. The mice were viable but exhibited poorly developed mammary glands with markedly reduced milk production; thus more than half of parous females were unable to support the lives of new born pups. The mammary glands of the MDTG mice had very low Ki-67 expression but high levels of Arf, Ink4a, p53, and p21Cip1, markers of senescence and accelerated aging. In all strains of generated MDTG;neu mice, tumor development was significantly delayed with decreased tumor weight. Tumors from MDTG;neu mice expressed Flag-Dmp1α and Ki-67 in a mutually exclusive fashion indicating that transgenic Dmp1α prevented tumor growth in vivo. Genomic DNA analyses showed that the Dmp1α transgene was partially lost in half of the MDTG;neu tumors, and Western blot analyses showed Dmp1α protein downregulation in 80% of the cases. Our data demonstrate critical roles of Dmp1 in preventing mammary tumorigenesis and raise the possibility of treating breast cancer by restoring Dmp1α expression.
Highlights
Breast cancer is one of the most important public health issues in the United States and most industrialized countries [1,2,3,4]
We recently found that loss of heterozygosity (LOH) of human DMP1 (hDMP1) was present in,35% of non-small cell lung carcinomas [30,35,36]
Establishment of mammary tumor virus (MMTV)-Flag-Dmp1a Mice To elucidate the roles of Dmp1a in mammary tumor development and prevention of human c-ErbB2 gene (HER2);neu-induced mammary carcinogenesis, we created transgenic mice that constitutively express the Flag-tagged murine Dmp1a gene under the control of the MMTV promoter (MMTV-Flag-Dmp1a, MMTV-Flag-Dmp1a transgenic (MDTG)) (Fig. S1; strain 138 results, not shown)
Summary
Breast cancer is one of the most important public health issues in the United States and most industrialized countries [1,2,3,4]. ER is the primary transcription factor driving oncogenesis in hormone receptor-positive breast cancers, and usually responsive to adjuvant hormonal therapy with antiestrogens or aromatase inhibitors, giving a more favorable prognosis [1]. ER-negative tumors are frequently associated with more aggressive disease with poorer clinical outcomes, including amplification of HER2 or c-Myc oncogenes or gain-of-function mutation of p53 [1,4]. BRCA1/2 are highpenetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutations of so-called low penetrance breast cancer genes functionally related to BRCA1/2, such as CHEK2, ATM, BRIP1, and PALB2, are rare, but confer an intermediate risk of the disease [5]
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