A subgroup of microRNAs defines PTEN-deficient, triple-negative breast cancer patients with poorest prognosis and alterations in RB1, MYC, and Wnt ... View Full Text


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Article Info

DATE

2019-01-31

AUTHORS

Dong-Yu Wang, Deena M. A. Gendoo, Yaacov Ben-David, James R. Woodgett, Eldad Zacksenhaus

ABSTRACT

BackgroundTriple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs.MethodsPublically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy.ResultsIn TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway.ConclusionsThis analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy. More... »

PAGES

18

References to SciGraph publications

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    43 schema:description BackgroundTriple-negative breast cancer (TNBC) represents a heterogeneous group of ER- and HER2-negative tumors with poor clinical outcome. We recently reported that Pten-loss cooperates with low expression of microRNA-145 to induce aggressive TNBC-like lesions in mice. To systematically identify microRNAs that cooperate with PTEN-loss to induce aggressive human BC, we screened for miRNAs whose expression correlated with PTEN mRNA levels and determined the prognostic power of each PTEN-miRNA pair alone and in combination with other miRs.MethodsPublically available data sets with mRNA, microRNA, genomics, and clinical outcome were interrogated to identify miRs that correlate with PTEN expression and predict poor clinical outcome. Alterations in genomic landscape and signaling pathways were identified in most aggressive TNBC subgroups. Connectivity mapping was used to predict response to therapy.ResultsIn TNBC, PTEN loss cooperated with reduced expression of hsa-miR-4324, hsa-miR-125b, hsa-miR-381, hsa-miR-145, and has-miR136, all previously implicated in metastasis, to predict poor prognosis. A subgroup of TNBC patients with PTEN-low and reduced expression of four or five of these miRs exhibited the worst clinical outcome relative to other TNBCs (hazard ratio (HR) = 3.91; P < 0.0001), and this was validated on an independent cohort (HR = 4.42; P = 0.0003). The PTEN-low/miR-low subgroup showed distinct oncogenic alterations as well as TP53 mutation, high RB1-loss signature and high MYC, PI3K, and β-catenin signaling. This lethal subgroup almost completely overlapped with TNBC patients selected on the basis of Pten-low and RB1 signature loss or β-catenin signaling-high. Connectivity mapping predicted response to inhibitors of the PI3K pathway.ConclusionsThis analysis identified microRNAs that define a subclass of highly lethal TNBCs that should be prioritized for aggressive therapy.
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    50 BackgroundTriple-negative breast cancer
    51 ConclusionsThis analysis
    52 ER
    53 HER2-negative tumors
    54 K pathway
    55 MYC
    56 PI3K
    57 PI3K pathway
    58 PTEN expression
    59 PTEN loss
    60 PTEN mRNA levels
    61 Rb1
    62 TNBC
    63 TNBC patients
    64 TNBC subgroup
    65 TP53 mutations
    66 Wnt
    67 aggressive therapy
    68 alterations
    69 analysis
    70 available data sets
    71 basis
    72 breast cancer
    73 breast cancer patients
    74 cancer
    75 cancer patients
    76 clinical outcomes
    77 cohort
    78 combination
    79 connectivity mapping
    80 cooperate
    81 correlates
    82 data sets
    83 defines
    84 expression
    85 genomic landscape
    86 genomics
    87 group
    88 heterogeneous group
    89 high MYC
    90 human BC
    91 independent cohort
    92 inhibitors
    93 landscape
    94 lesions
    95 levels
    96 loss
    97 low expression
    98 mRNA
    99 mRNA levels
    100 mapping
    101 metastasis
    102 miR
    103 miRNAs
    104 mice
    105 microRNA-145
    106 microRNAs
    107 mutations
    108 oncogenic alterations
    109 outcomes
    110 pairs
    111 pathway
    112 patients
    113 poor clinical outcome
    114 poor prognosis
    115 power
    116 prognosis
    117 prognostic power
    118 reduced expression
    119 response
    120 set
    121 signaling
    122 signatures
    123 subclasses
    124 subgroups
    125 therapy
    126 triple-negative breast cancer patients
    127 tumors
    128 worse clinical outcomes
    129 β-catenin
    130 β-catenin signaling
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