Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors

Tell, Robert; Horvath, Curt M.

doi:10.1073/pnas.1404881111

Cited by 49 publications

(47 citation statements)

References 35 publications

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“…However, it did not describe direct gene signatures regulated by STAT3, nor functional characterization of the role of STAT3 in invasion in TNBC. Our work builds on this study as we further uncovered gene signatures likely regulated by STAT3 that corroborates the functional enrichments described by independent studies [32]. Moreover, we provide functional data to support a role for STAT3 in the regulation of cellular invasion processes in TNBC.…”

Section: Discussionsupporting

confidence: 85%

Genomic regulation of invasion by STAT3 in triple negative breast cancer

et al. 2016

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Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as “triple negative breast cancer” (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 5 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.

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Section: Discussionsupporting

confidence: 85%

Genomic regulation of invasion by STAT3 in triple negative breast cancer

et al. 2016

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“…These data suggest that ADAM12 in BTC can activate tumor or endothelial cells within the tumor microenvironment. Bioinformatics analysis has identified STAT3-regulated signaling pathways in more aggressive basal-like breast cancers (48). STAT3 is a direct transcriptional activator of VEGF (30,31), and persistently activated STAT3 can transform human mammary epithelial cells via significantly increased MMP-9 activity (49).…”

Section: Discussionmentioning

confidence: 99%

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

Roy

Dagher

Butterfield

et al. 2017

Molecular Cancer Research

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ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our aim was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue inhibitor of metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.

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“…RPPA proteomic signal pathway patterns can complement mRNA pattern analysis of clinical response and histopathologic subtypes for a more complete understanding of the true drivers of the malignant process [75]. To address the lack of response to chemotherapy in children with rhabdomyosarcoma, Petricoin et al [21]utilized RPPA to provide a phosphoproteomic network analysis of microdissected tumor cells.…”

Section: Rppa and Cancer Profilingmentioning

confidence: 99%

Reverse Phase Protein Arrays: Mapping the Path Towards Personalized Medicine

Gallagher

Espina

2014

Mol Diagn Ther

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Reverse phase protein array (RPPA) technology evolved from the advent of miniaturized immunoassays and gene microarray technology. Reverse phase protein arrays provide either a low throughput or high throughput methodology for quantifying proteins and their post-translationally modified forms in both cellular and non-cellular samples. As the demand for patient tailored therapies increases so does the need for precise and sensitive technology to accurately profile the molecular circuitry driving an individual patient’s disease. RPPAs are currently utilized in clinical trials for profiling and comparing the functional state of protein signaling pathways, either temporally within tumors, between patients, or within the same patients before/after treatment. RPPAs are generally employed for quantifying large numbers of samples on one array, under identical experimental conditions. However, the goal of personalized cancer medicine is to design therapies based on the molecular portrait of a patient’s tumor, which in turn result in more efficacious treatments with less toxicity. Therefore, RPPAs are also being validated for low throughput assays of individual patient samples. This review explores reverse phase protein array technology in the cancer research field, concentrating on its role as a fundamental tool for deciphering protein signaling networks and its emerging role in personalized medicine.

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Bioinformatic analysis reveals a pattern of STAT3-associated gene expression specific to basal-like breast cancers in human tumors

Cited by 49 publications

References 35 publications

Genomic regulation of invasion by STAT3 in triple negative breast cancer

Genomic regulation of invasion by STAT3 in triple negative breast cancer

ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling

Reverse Phase Protein Arrays: Mapping the Path Towards Personalized Medicine

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