Overall, our findings suggest that PPM1D contributes to breast cancer associated phenotypic characteristics by directly or indirectly affecting several important cellular signaling pathways.
We observed limited evidence for an association between mosaic PPM1D PTVs and breast cancer risk, suggesting mosaic PPM1D PTVs in the blood likely do not influence risk of breast cancer.
PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)).
The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D.
These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.
Our findings demonstrate that PPM1D is involved in the regulation of cell proliferation in breast cancer in a p53-dependent manner and that overexpression of PPM1D contributes to malignant phenotype by promoting sustained cell growth and cell survival.
To explore wild-type p53-independent Wip1 induction, Wip1 promoter activity and its transcript level were evaluated by luciferase assay and real-time PCR, after methylmethane sulfonate (MMS) treatment in breast cancer cell lines and p53-null cell lines.
PVs indicative of CH (ATM, NBN, and PPM1D [x2]) were identified in three of 27 individuals with breast cancer who received chemotherapy and in one healthy control.
These results indicate that Wip1 up-regulation is important in the pathogenesis of p53(+) and ER(+) breast cancer through the inactivation of p53 by dephosphorylation and the amplification of subsequent estrogenic effects through the E(2)-ERalpha-Wip1 pathway.
Three of the 20 PPM1D carrier case patients had a past history of breast cancer compared with 29 of 1129 noncarriers (OR = 6.69; 95% CI = 1.86 to 24.11; P = .007).
Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established.
Overexpression of miR-16 or inhibition of Wip1 suppresses the self-renewal and growth of mouse mammary tumor stem cells and sensitizes MCF-7 human breast cancer cells to the chemotherapeutic drug doxorubicin.