Pregnancy‐associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer

• DOI: 10.1002/path.4393
• Publication Date: 2014-06-13T17:37:23Z
• Authors: Marco Loddo; Joanna Andryszkie...; Sara Rodriguez‐Ac...; Kai Stoeber; Allison Jones; Dimitra Dafou; Sophia Apostolidou; Alex Wollenschlaeger; Martin Widschwendter; Richard Sainsbury; Slavica Tudzarova; Gareth Haydn Will...
• Keywords: Prometaphase; FOXM1

Aberrant mitosis is a common feature of cancer, yet little known about the altered genes causing mitotic defects. We screened human tumours for cells with morphological signatures highly specific defects previously assigned to candidate in genome-wide RNA interference screen carried out HeLa (www.mitocheck.org). discovered striking enrichment early configurations indicative prophase/prometaphase delay breast cancer. Promoter methylation analysis MitoCheck corresponding 'mitotic delay' class linked this defect epigenetic silencing gene encoding pregnancy-associated plasma protein-A (PAPPA), secreted protease. PAPPA was prevalent precursor lesions and invasive Experimental manipulation protein levels mammary epithelial cancer cell lines demonstrates that progression through dependent on function, become more after down-regulation regulates modulating IGF-1 signalling pathway resulting activation forkhead transcription factor FoxM1, which drives transcriptional cluster essential genes. Our results show has critical function normal division targeted development.