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- Title
Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas.
- Authors
Geyer, Felipe C.; Anqi Li; Papanastasiou, Anastasios D.; Smith, Alison; Selenica, Pier; Burke, Kathleen A.; Edelweiss, Marcia; Huei-Chi Wen; Piscuoglio, Salvatore; Schultheis, Anne M.; Martelotto, Luciano G.; Pareja, Fresia; Kumar, Rahul; Brandes, Alissa; Dan Fan; Basili, Thais; Da Cruz Paula, Arnaud; Lozada, John R.; Blecua, Pedro; Muenst, Simone
- Abstract
Adenomyoepithelioma of the breast is a rare tumor characterized by epithelial-myoepithelial differentiation, whose genetic underpinning is largely unknown. Here we show through whole-exome and targeted massively parallel sequencing analysis that whilst estrogen receptor (ER)-positive adenomyoepitheliomas display PIK3CA or AKT1 activating mutations, ER-negative adenomyoepitheliomas harbor highly recurrent codon Q61 HRAS hotspot mutations, which co-occur with PIK3CA or PIK3R1 mutations. In two- and three-dimensional cell culture models, forced expression of HRASQ61R in non-malignant ER-negative breast epithelial cells with or without a PIK3CAH1047R somatic knock-in results in transformation and the acquisition of the cardinal features of adenomyoepitheliomas, including the expression of myoepithelial markers, a reduction in E-cadherin expression, and an increase in AKT signaling. Our results demonstrate that adenomyoepitheliomas are genetically heterogeneous, and qualify mutations in HRAS, a gene whose mutations are vanishingly rare in common-type breast cancers, as likely drivers of ER-negative adenomyoepitheliomas.
- Subjects
BREAST; ESTROGEN receptors; CELL culture; EPITHELIAL cells; GENES; CANCER cell culture
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-04128-5