title: Comparison of the PI3KCA pathway in circulating tumor cells and corresponding tumor tissue of patients with metastatic breast cancer.
abstract: The aim of the present study was to compare the phosphatidylinositol 3-kinase (PI3KCA)-AKT serine/threonine kinase (AKT) pathway in circulating tumor cells (CTCs) and corresponding cancerous tissues. Stemness‑like circulating tumor cells (slCTCs) and CTCs in epithelial-mesenchymal transition (EMT) have been implicated as the active source of metastatic spread in breast cancer (BC). In this regard, the PI3KCA‑AKT signaling pathway was demonstrated to be implicated in and to be frequently mutated in BC. The present study compared this pathway in slCTCs/CTCs in EMT and the corresponding tumor tissues of 90 metastatic BC patients (pts). slCTCs and CTCs in EMT were isolated using the AdnaTest EMT-1/StemCell for the detection of aldehyde dehydrogenase 1 family member A1 (ALDH1) (singleplex PCR) and PI3KCA, AKT2 and twist family bHLH transcription factor 1 (multiplex PCR). Tumor tissue was investigated for PI3KCA hotspot mutations using Sanger sequencing of genomic DNA from micro‑dissected formalin‑fixed paraffin‑embedded tissue, and for the expression of ALDH1 and phosphorylated AKT (pAKT), and phosphatase and tensin homolog (PTEN) loss, by immunohistochemistry. slCTCs were identified in 23% of pts (21/90 pts) and CTCs in EMT in 56% (50/90 pts) of pts. pAKT and ALDH1 positivity in tumor tissue was identified in 47 and 9% of cases, respectively, and a PTEN loss was observed in 18% of pts. A significant association was detected between pAKT expression in cancerous tissue and AKT2 expression in CTCs (P=0.037). PI3KCA mutations were detected in 32% of pts, most frequently on exons 21 (55%) and 10 (45%). Pts with PI3KCA mutations in tumor tissue had a significantly longer overall survival than pts with wild-type PI3KCA expression (P=0.007). Similar results were obtained for pts with aberrant PI3KCA signaling in CTCs and/or aberrant signaling in cancerous tissue (P=0.009). Therapy‑resistant CTCs, potentially derived from the primary tumor or metastatic tissue, may be eliminated with specific PI3K pathway inhibitors, alone or in combination, to improve the prognosis of metastatic BC pts.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Bredemeier
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kasimir-Bauer
authors.affiliation: Department of Gynecology and Obstetrics, Marienhospital Bottrop, D‑46236 Bottrop, Germany.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Kolberg
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Herold
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Synoracki
authors.affiliation: Qiagen Hannover GmbH, D‑30853 Langenhagen, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hauch
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Philippos
authors.initials: P
authors.lastname: Edimiris
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bankfalvi
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Mitra
authors.initials: M
authors.lastname: Tewes
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany.
authors.forename: Bahriye
authors.initials: B
authors.lastname: Aktas
mesh_terms: D000328:Adult; D000368:Aged; D000080924:Aldehyde Dehydrogenase 1 Family; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D007527:Isoenzymes; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase