Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy

Kim

et al. 2018

Intl Journal of Cancer

The histone H3 lysine 4-specific methyltransferase SETD1A is associated with transcription activation and is considered a key epigenetic regulator that modulates the cell cycle and metastasis in triple-negative breast cancer cells. However, the clinical role of SETD1A in estrogen receptor (ER)-positive breast cancer cells remains unclear. Here, we examined whether SETD1A is a potential target for ERα-positive breast cancer therapy. SETD1A expression was upregulated in breast tumor tissue compared to that in normal breast tissue. Moreover, ER-target genes regulated by SETD1A were particularly enriched in cell cycle and cancer pathways. SETD1A is involved in histone H3K4 methylation, subsequent recruitment of ERα, and the establishment of accessible chromatin structure at the enhancer region of ERα target genes. In addition to ERα target genes, other cell survival genes were also downregulated by SETD1A depletion in MCF-7 cells, leading to significant decrease in cell proliferation and migration, and spontaneous induction of apoptosis. We also found that miR-1915-3p functioned as a novel regulator of SETD1A expression in breast cells. Importantly, the growth of tamoxifen-resistant MCF-7 cells was effectively repressed by SETD1A knockdown. These results indicate that SETD1A may serve as a molecular target and prognostic indicator in ERα-positive breast cancer.

Section: Resultsmentioning

confidence: 91%

Aberrant expression of SETD1A promotes survival and migration of estrogen receptor α‐positive breast cancer cells

Kim

et al. 2018

Intl Journal of Cancer

Clinical Cancer Research

“…Such evaluation of gene expression provides unprecedented insight into biological processes that occur in tissue. Like morphologic assessments, molecular data are shaped by tumor-driving mutations, tissue heterogeneity, disease progression, or selective pressures from treatment (14)(15)(16). Technical issues may further affect interpretation: in breast cancer, significant differences were identified between diagnostic tissue core biopsies when compared with tumor excisions.…”

Section: Introductionmentioning

confidence: 99%

Head and Neck Squamous Cell Carcinomas Are Characterized by a Stable Immune Signature Within the Primary Tumor Over Time and Space

Wood

Clarke

Woo

et al. 2017

Genetic and morphologic heterogeneity is well-documented in solid cancers. Immune cells are also variably distributed within the tumor; this heterogeneity is difficult to assess in small biopsies, and may confound our understanding of the determinants of successful immunotherapy. We examined the transcriptomic variability of the immunologic signature in head and neck squamous cell carcinoma (HNSCC) within individual tumors using transcriptomic and IHC assessments. Forty-four tumor biopsies from 16 HNSCC patients, taken at diagnosis and later at resection, were analyzed using RNA-sequencing. Variance filtering was used to identify the top 4,000 most variable genes. Principal component analysis, hierarchical clustering, and correlation analysis were performed. Gene expression of was correlated to IHC analysis. Analysis of immunologic gene expression was highly consistent in replicates from the same cancer. Across the cohort, samples from the same patient were most similar to each other, both spatially (at diagnosis) and, notably, over time (diagnostic biopsy compared with resection); comparison of global gene expression by hierarchical clustering ( ≤ 0.0001) and correlation analysis [median intrapatient = 0.82; median interpatient = 0.63]. gene transcript counts were highly correlated with CD8 T-cell counts by IHC ( = 0.82). Our data demonstrate that in HNSCC the global tumor and adaptive immune signatures are stable between discrete parts of the same tumor and also at different timepoints. This suggests that immunologic heterogeneity may not be a key reason for failure of immunotherapy and underpins the use of transcriptomics for immunologic evaluation of novel agents in HNSCC patients. .

“…Furthermore, the ability of a subset of breast tumors to alter their molecular profile between primary and recurrent tumors is the subject of intense investigation [26, 31]. This tumor adaptability is controlled, at least in part, through transcription factors including HOX family members responding to the therapeutic environment [3, 32, 33].…”

Section: Discussionmentioning

confidence: 99%

“…Mouse experiments were performed as previously described [26]. Endocrine sensitive (MCF-7) and endocrine resistant (LY2) xenograft models were established.…”

Section: Methodsmentioning

confidence: 99%

S100β as a serum marker in endocrine resistant breast cancer

Charmsaz

Hughes

Bane

et al. 2017

BMC Med

Self Cite

BackgroundEndocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated.MethodsThe expression of S100β in tissue and serum was assessed by immunohistochemistry and an enzyme-linked immunosorbent assay, respectively. The S100β signaling network was investigated in cell line models of endocrine resistance by western blot, PCR, immunoprecipitation, and chromatin-immunoprecipitation. Endocrine resistant xenografts and tumor explants from patients with resistant tumors were treated with endocrine therapy in the presence and absence of the p-Src kinase inhibitor, dasatinib.ResultsTissue and serum levels of S100β were found to predict poor disease-free survival in endocrine-treated patients (n = 509, HR 2.32, 95% CI is 1.58–3.40, p < 0.0001 and n = 187, HR 4.009, 95% CI is 1.66–9.68, p = 0.002, respectively). Moreover, elevated levels of serum S100β detected during routine surveillance over the patient treatment period significantly associated with subsequent clinically confirmed disease recurrence (p = 0.019). In vivo studies demonstrated that endocrine treatment induced transcriptional regulation of S100β which was successfully disrupted with tyrosine kinase inhibition. In endocrine resistant xenografts and tumor explants from patients with endocrine resistant breast cancer, combined endocrine and dasatinib treatment reduced tumor proliferation and down-regulated S100β protein expression in comparison to endocrine treatment alone.ConclusionsS100β has potential as a new surveillance tool for patients with ER-positive breast cancer to monitor ongoing response to endocrine therapy. Moreover, endocrine resistant breast cancer patients with elevated S100β may benefit from combined endocrine and tyrosine-kinase inhibitor treatment.Trial registrationClinicalTrials.gov, NCT01840293). Registered on 23 April 2013. Retrospectively registered.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0836-2) contains supplementary material, which is available to authorized users.