Background: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated.
Methods: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively.
Results: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression.
Conclusions: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC.
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This study was funded by the U.S. National Institutes of Health (Medical Scientist Training Grant 5 T32 GM07367-29 [LHS], R01 CA175105 [Q-BS], P01 CA097403 and R01 CA082783 [RP], P01 CA094060 [NR]), Stand Up To Cancer Dream Team (MM, NR, RP), the Avon Foundation (HH and RP), and the Swedish Cancer Society, Swedish Research Council, Governmental Funding of Clinical Research within National Health Service, Mrs. Berta Kamprad Foundation, Skåne University Hospital Foundation, King Gustav V’s Jubilee Foundation, Krapperup Foundation, Gunnar Nilsson Cancer Foundation, and Crafoord Foundation (all to LHS).
Data and materials may be requested from the corresponding author. Microarray data are publicly available from the NCBI Gene Expression Omnibus under accession GSE74667.
She, Qing-Bai; Gruvberger-Saal, Sofia K.; Maurer, Matthew; Chen, Yilun; Jumppanen, Mervi; Su, Tao; Dendy, Meaghan; Lau, Ying-Ka Ingar; Memeo, Lorenzo; Horlings, Hugo M.; van de Vijver, Marc J.; Isola, Jorma; Hibshoosh, Hanina; Rosen, Neal; Parsons, Ramon; and Saal, Lao H., "Integrated Molecular Pathway Analysis Informs a Synergistic Combination Therapy Targeting PTEN/PI3K and EGFR Pathways for Basal-Like Breast Cancer" (2016). Markey Cancer Center Faculty Publications. 72.