Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

Bollig‐Fischer, Aliccia; Michelhaugh, Sharon K.; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adéle; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

doi:10.18632/oncotarget.3786

Cited by 30 publications

(19 citation statements)

References 38 publications

(24 reference statements)

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“…In recent years, comparative genomic hybridization (CGH) array chips have become a useful tool in detecting and mapping gene CNV [ 18 ]. To provide an overview of CNV in the leukocyte genome of HBV-HCC patients, we employed CGH array chips to analyze peripheral blood mononuclear cells (PBMCs) from 10 HCC patients who were HBV carriers.…”

Section: Introductionmentioning

confidence: 99%

Gene copy number variations in the leukocyte genome of hepatocellular carcinoma patients with integrated hepatitis B virus DNA

et al. 2016

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Integration of hepatitis B virus (HBV) DNA into the human liver cell genome is believed to promote HBV-related carcinogenesis. This study aimed to quantify the integration of HBV DNA into the leukocyte genome in hepatocellular carcinoma (HCC) patients in order to identify potential biomarkers for HBV-related diseases. Whole-genome comparative genomic hybridization (CGH) chip array analyses were performed to screen gene copy number variations (CNV) in the leukocyte genome, and the results were confirmed by quantitative polymerase chain reaction (qPCR). The commonly detected regions included chromosome arms 19p, 5q, 1q and 15p, where 200 copy number gain events and 270 copy number loss events were noted. In particular, gains were observed in 5q35.3 (OR4F3) and 19p13.3 (OR4F17) in 90% of the samples. Successful homologous recombination of OR4F3 and the HBV P gene was demonstrated, and the amplification at 5q35.3 is potentially associated with the integration of HBV P gene into natural killer cells isolated from peripheral blood mononuclear cells (PBMCs). Receiver operating characteristic (ROC) curve analysis indicated that the combination of OR4F3 and OR4F17 a novel potential biomarker of HBV-related diseases.

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Section: Introductionmentioning

confidence: 99%

Gene copy number variations in the leukocyte genome of hepatocellular carcinoma patients with integrated hepatitis B virus DNA

et al. 2016

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“…Silva et al suggests that increased activation of HER3 and its downstream MAPK/AKT pathway molecules are implicated in colonization of brain metastasis [ 12 ]. Bolling-Fischer et al showed the amplified oncogenes including SOX2, PIK3CA, NTRK1, GNAS, CTNNB1 , and FGFR1 are related to the Stem Cell Pluripotency pathway [ 13 ]. Saunus et al identified novel candidates with possible roles in BCBM development including the significantly mutated genes DSC2, ST7, PIK3R1 , and SMC5 [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer

et al. 2015

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Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0–7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

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“…Consistent with the notion that stemness and embryonic pathways can play oncogenic roles, SOX2 expression was documented in several cancers, especially of endodermal, epithelial and neural origin [ 3 – 13 ]. In the breast, SOX2 expression has not been reported in healthy tissues but is detectable across different breast carcinoma (BC) subtypes [ 14 ] and particularly prominent also in certain BC-derived metastases [ 15 ]. Interestingly, SOX2 expression in BC is mostly confined to a minor subset of tumor cells and detectable at early stages of the disease as well as at relapse, suggesting that it is involved in BC stem cell biology and might represent a genetic driver event [ 14 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular and functional interactions between AKT and SOX2 in breast carcinoma

et al. 2015

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The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT-inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC.

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Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

Cited by 30 publications

References 38 publications

Gene copy number variations in the leukocyte genome of hepatocellular carcinoma patients with integrated hepatitis B virus DNA

Gene copy number variations in the leukocyte genome of hepatocellular carcinoma patients with integrated hepatitis B virus DNA

Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer

Molecular and functional interactions between AKT and SOX2 in breast carcinoma

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