Disruption of Estrogen Signaling Enhances Invasiveness of Breast Cancer Cells by Attenuating a HER2-independent Gene Repression Program
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE53734 | GEO | 2016/11/01
SECONDARY ACCESSION(S): PRJNA232771
REPOSITORIES: GEO
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Project description:A subset of HER2 breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2g. We sought to define AP-2g-regulated genes that control growth and invasiveness by comparing HER2 cell lines with differential response to TFAP2C knockdown. A set of 68 differentially expressed genes was identified, which included CDH5 and CDKN1A. Pathway analysis implicated the MAPK13/p38δ and retinoic acid regulatory nodes, which were confirmed to display divergent responses. The AP-2g gene signature was highly predictive of outcome in HER2-positive breast cancer patients. We conclude that AP-2g regulates a set of genes in HER2 breast cancer that drive cancer growth and invasiveness and that the AP-2g gene signature can predict outcome of patients with HER2 breast cancer.
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Project description:Our findings demonstrate that CDCP1 is a novel modulator of HER2 signalling, and a biomarker for the stratification of breast cancer patients with poor prognosis
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Project description:Abstract: A subset of HER2 breast cancers with amplification of the TFAP2C gene locus becomes addicted to AP-2g. We sought to define AP-2g-regulated genes that control growth and invasiveness by comparing HER2 cell lines with differential response to TFAP2C knockdown. A set of 68 differentially expressed genes was identified, which included CDH5 and CDKN1A. Pathway analysis implicated the MAPK13/p38δ and retinoic acid regulatory nodes, which were confirmed to display divergent responses. The AP-2g gene signature was highly predictive of outcome in HER2-positive breast cancer patients. We conclude that AP-2g regulates a set of genes in HER2 breast cancer that drive cancer growth and invasiveness and that the AP-2g gene signature can predict outcome of patients with HER2 breast cancer. Results: Using an optimized data analysis workflow, we mapped about 50-75 million sequence reads per sample to the human genome Human Feb.2009 (GRCh37/hg19) (hg19). By RNA-seq analysis, knockdown of TFAP2C in HCC1954 with siRNA (compared to NT siRNA) identified 364 genes with significantly altered expression. To further create specificity for AP-2gamma-regulated genes, RNA-seq analysis was performed comparing expression in shHCC1954 with shTFAP2C cells vs. shNT; this analysis identified 8,986 genes with significantly altered expression. The two data sets were subsequently compared to identify a set of genes that were consistently altered with knockdown of TFAP2C by siRNA and shRNA. This comparison confirmed the identification of 152 AP-2gamma target genes in HCC1954 cells. Because HCC1954 demonstrated opposite growth regulation and invasiveness with knockdown of TFAP2C compared to SKBR3, we hypothesized that the AP-2gamma target genes responsible for growth and invasion would be differentially regulated with knockdown of TFAP2C in HCC1954 versus SKBR3. Hence, RNA-seq analysis was performed in SKBR3 after knockdown of TFAP2C with siRNA; in this analysis, a total of 3814 genes were significantly altered. The pattern of expression for the 152 AP-2gamma target genes identified in HCC1954 was subsequently compared to expression changes in SKBR3. Of note, only 79 of the 152 TFAP2C target genes in HCC1954 were found to change expression significantly in the RNA-seq data set from SKBR-3. Conclusions: Knockdown of TFAP2C with co-knockdown of CDH5 in SKBR-3 confirmed no significant effect on invasion, though there was a slight reduction in invasiveness with knockdown of CDH5 that failed to reach statistical significance (p=0.12). These findings support the conclusion that regulation of CDH5 and CDKN1A contribute to alterations of proliferation and invasiveness induced by knockdown of TFAP2C.
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Project description:The acquisition of cell invasiveness is the key transition from benign melanocyte hyperplasia to aggressive melanoma. Recent work using non-melanoma cancer cells has provided an intriguing new link between the presence of supernumerary centrosomes and increased cell invasion. Moreover, supernumerary centrosomes were shown to drive non-cell-autonomous invasion of cancer cells. Although centrosomes are the principle microtubule organizing centers the role of dynamic microtubules for non-cell-autonomous invasion remains unexplored, in particular in melanoma. We investigated the role of supernumerary centrosomes and dynamic microtubules in melanoma cell invasion and found that highly invasive melanoma cells are characterized by the presence of supernumerary centrosomes and by increased microtubule growth rates, both of which are functionally interlinked. We demonstrate that enhanced microtubule growth is required for increased 3D melanoma cell invasion. Moreover, we show that the activity to enhance microtubule growth can be transferred to adjacent non-invasive cells through extracellular vesicles harboring HER2 that are required for increased cell invasion of melanoma cells into 3D matrices. Hence, our study suggests that suppressing microtubule growth, either directly using anti-microtubule drugs or through HER2 inhibitors might be therapeutically beneficial to inhibit cell invasiveness and thus, metastasis of malignant melanoma.
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Project description:Breast cancer is a heterogeneous disease encompassing a number of phenotypically diverse tumours. Expression levels of the estrogen, progesterone and HER2/neu receptors which characterise clinically distinct breast tumors have been shown to change during disease progression and in response to systemic therapies. Mi(cro)RNAs play critical roles in diverse biological processes and are aberrantly expressed in several human neoplasms including breast cancer, where they function as regulators of tumour behaviour and progression. The aims of this study were to identify miRNA signatures that accurately predict the oestrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor status of breast cancer patients to provide insight into the regulation of breast cancer phenotypes and progression. Expression profiling of 353 microRNAs was performed in 29 early stage breast cancer specimens. MiRNA signatures associated with ER, PR and HER2/neu status were generated using artificial neural networks (ANN) and expression of specific microRNAs was validated using RQ-PCR. Results: Stepwise artificial neural network (ANN) analysis identified predictive miRNA signatures corresponding with estrogen (miR-342, miR-299, miR-217, miR -190, miR-135b, miR-218), progesterone (miR-520g, miR-377, miR-527-518a, miR-520f-520c) and HER2/neu (miR-520d, miR-181c, miR-302c, miR-376b, miR-30e) receptor status. MiR-342 and miR-520g expression was further analysed in 95 breast tumours. MiR-342 expression was highest in ER and HER2/neu positive luminal B tumours and lowest in triple-negative tumours. MiR-520g expression was elevated in ER and PR negative tumours.
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