Details

Autor(en) / Beteiligte

• Pierobon, Mariaelena
• Ramos, Corinne
• Wong, Shukmei
• Hodge, K Alex
• Aldrich, Jessica
• Byron, Sara
• Anthony, Stephen P
• Robert, Nicholas J
• Northfelt, Donald W
• Jahanzeb, Mohammad
• Vocila, Linda
• Wulfkuhle, Julia
• Gambara, Guido
• Gallagher, Rosa I
• Dunetz, Bryant
• Hoke, Nicholas
• Dong, Ting
• Craig, David W
• Cristofanilli, Massimo
• Leyland-Jones, Brian
• Liotta, Lance A
• O'Shaughnessy, Joyce A
• Carpten, John D
• Petricoin, Emanuel F

Titel

Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Ist Teil von

• Clinical cancer research, 2017-08, Vol.23 (16), p.4919-4928

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2017

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis. Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions. mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions ( < 0.01, = 0.056, and = 0.053, respectively). However, mutations alone were insufficient in predicting protein activation ( = 0.32 and = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); < 0.01, = 0.02, and = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) < 0.01, mTOR (S2448) < 0.01, 4EBP1 (S65) = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined. Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of mutations and activation of the PI3K-AKT-mTOR signaling network. .