Abstract
BackgroundThe 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.MethodsOne 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.ResultsSixty-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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2609-2) contains supplementary material, which is available to authorized users.
Highlights
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 four most discernible subtypes by gene expression profiling include the two estrogen-receptor (ER)-positive subtypes, luminal A and B which are characterized by low and high proliferation, respectively; the HER2 subtype characterized by overexpression of genes in the HER2 (ERBB2) amplicon; and the basal-like Breast cancer (BC) (BLBC) subtype characterized by expression of basallyoriented mammary epithelial cell markers such as cytokeratins 5 and 14 (CK5/14), lack of hormone receptors and HER2 expression (“triple-negative”), and high genomic instability [1]
The tumor suppressor PTEN, a lipid phosphatase acting in direct enzymatic opposition to phosphatidylinositol 3-kinase (PI3K), is infrequently inactivated by mutations in sporadic BC (5 %), PTEN protein expression is significantly reduced in ~25 % breast tumors, more commonly in ERnegative cancer and in particular within BLBC, and rarely coinciding with PIK3CA mutation [2, 7]
Summary
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. PTEN is frequently grossly mutated in BRCA1-hereditary BC, a group of tumors that usually exhibit the basal-like phenotype [7, 8], and new nuclear roles for PTEN in maintaining genome stability have been identified. Another lipid phosphatase, inositol polyphosphate 4-phosphatase type II (INPP4B), has recently been shown to have potential tumor suppressor activity [9, 10]. Constitutive activation of PI3K pathway by PTEN mutation/loss or PIK3CA mutation could render tumor cells independent of RTKs for malignant transformation and maintenance, which leads to resistance to HER2-targeted therapies in BC and EGFR-targeted therapies in glioma [15,16,17,18,19,20]
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