Dataset Information

Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas.

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.

SUBMITTER: Geyer FC

PROVIDER: S-EPMC5940840 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas.

Geyer Felipe C FC Li Anqi A Papanastasiou Anastasios D AD Smith Alison A Selenica Pier P Burke Kathleen A KA Edelweiss Marcia M Wen Huei-Chi HC Piscuoglio Salvatore S Schultheis Anne M AM Martelotto Luciano G LG Pareja Fresia F Kumar Rahul R Brandes Alissa A Fan Dan D Basili Thais T Da Cruz Paula Arnaud A Lozada John R JR Blecua Pedro P Muenst Simone S Jungbluth Achim A AA Foschini Maria P MP Wen Hannah Y HY Brogi Edi E Palazzo Juan J Rubin Brian P BP Ng Charlotte K Y CKY Norton Larry L Varga Zsuzsanna Z Ellis Ian O IO Rakha Emad A EA Chandarlapaty Sarat S Weigelt Britta B Reis-Filho Jorge S JS

Nature communications 20180508 1

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- an ...[more]

PMID: 29739933

Similar Datasets

Project description:Breast cancer is the most prevalent type of cancer among women. Several types of drugs, targeting the specific proteins expressed on the breast cancer cell surface (such as receptor tyrosine kinases and immune checkpoint regulators) and proteins involved in cell cycle and motility (including cyclin-dependent kinases, DNA stabilisers, and cytoskeleton modulators) are approved for different subtypes of breast cancer. However, breast cancer also has a poor response to conventional chemotherapy due to intrinsic and acquired resistance, and an Akt fingerprint is detectable in most drug-resistant cases. Overactivation of Akt and its upstream and downstream regulators in resistant breast cancer cells is considered a major potential target for novel anti-cancer therapies, suggesting that Akt signalling acts as a cellular mechanism against chemotherapy. The present review has shown that sustained activation of Akt results in resistance to different types of chemotherapy. Akt signalling plays a cellular defence role against chemotherapy and (1) enhances multi-drug resistance, (2) increases reactive oxygen species at breast tumor microenvironment, (3) enhances anaerobic metabolism, (4) inhibits the tricarboxylic cycle, (5) promotes PD-L1 upregulation, (6) inhibits apoptosis, (7) increases glucose uptake, and more importantly (8) recruits and interconnects the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria to hijack breast cancer cells and rescue these cells from chemotherapy. Therefore, Akt signalling is considered a cellular defence mechanism employed against chemotherapeutic effects. In addition, interfering roles of PI3K/Akt signalling on the current cytotoxic and molecularly targeted therapy as well as immunotherapy of breast cancer are discussed with a clinical approach. Although, alpelisib, a PIK3CA inhibitor, is the only PI3K/Akt pathway inhibitor approved for breast cancer, we also highlight well-evaluated inhibitors of PI3K/Akt signalling based on different subtypes of breast cancer, which are under clinical trials whether as monotherapy or in combination with other types of chemotherapy.

Dataset Information

Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas.

Publications

Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets