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Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status.

ABSTRACT: The tumor suppressor p53 is the most frequently mutated gene in human cancers, mutated in 25-30% of breast cancers. However, mutation rates differ according to breast cancer subtype, being more prevalent in aggressive estrogen receptor-negative tumors and basal-like and HER2-amplified subtypes. This heterogeneity suggests that p53 may function differently across breast cancer subtypes. We used RNAi-mediated p53 knockdown (KD) and antagomir-mediated KD of microRNAs to study how gene expression and cellular response to p53 loss differ in luminal versus basal-like breast cancer. As expected, p53 loss caused downregulation of established p53 targets (e.g. p21 and miR-34 family) and increased proliferation in both luminal and basal-like cell lines. However, some p53-dependent changes were subtype specific, including expression of miR-134, miR-146a and miR-181b. To study the cellular response to miR-146a upregulation in p53-impaired basal-like lines, antagomir KD of miR-146a was performed. KD of miR-146a caused decreased proliferation and increased apoptosis, effectively ablating the effects of p53 loss. Furthermore, we found that miR-146a upregulation decreased NF-?B expression and downregulated the NF-?B-dependent extrinsic apoptotic pathway (including tumor necrosis factor, FADD and TRADD) and antagomir-mediated miR-146a KD restored expression of these components, suggesting a plausible mechanism for miR-146a-dependent cellular responses. These findings are relevant to human basal-like tumor progression in vivo, since miR-146a is highly expressed in p53 mutant basal-like breast cancers. These findings suggest that targeting miR-146a expression may have value for altering the aggressiveness of p53 mutant basal-like tumors.

SUBMITTER: Sandhu R

PROVIDER: S-EPMC4288116 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status.

Sandhu Rupninder R Rein Jessica J D'Arcy Monica M Herschkowitz Jason I JI Hoadley Katherine A KA Troester Melissa A MA

Carcinogenesis 20140814 11

The tumor suppressor p53 is the most frequently mutated gene in human cancers, mutated in 25-30% of breast cancers. However, mutation rates differ according to breast cancer subtype, being more prevalent in aggressive estrogen receptor-negative tumors and basal-like and HER2-amplified subtypes. This heterogeneity suggests that p53 may function differently across breast cancer subtypes. We used RNAi-mediated p53 knockdown (KD) and antagomir-mediated KD of microRNAs to study how gene expression an ...[more]

PMID: 25123132

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Project description:BACKGROUND/PURPOSE:TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. EXPERIMENTAL DESIGN/METHODS:To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. RESULTS:TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. CONCLUSIONS:Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.

Dataset Information

Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status.

Publications

Overexpression of miR-146a in basal-like breast cancer cells confers enhanced tumorigenic potential in association with altered p53 status.

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