Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

Gordon, Vallerie; Banerji, Shantanu

doi:10.1158/1078-0432.ccr-12-0274

Cited by 55 publications

(40 citation statements)

References 59 publications

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“…Pharmacological inhibition of both the ERK and AKT signaling pathways, but not either pathway alone, induces TNBC cell death [10, 21]. We previously showed that CIB1 depletion impaired both ERK and AKT activation, leading to significant cell death in MDA-MB-468 cells [10].…”

Section: Resultsmentioning

confidence: 99%

CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer

Black

Harrell

Leisner

et al. 2015

Breast Cancer Res Treat

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Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with generally poor prognosis and no available targeted therapies, highlighting a critical unmet need to identify and characterize novel therapeutic targets. We previously demonstrated that CIB1 is necessary for cancer cell survival and proliferation via regulation of two oncogenic signaling pathways, RAF–MEK–ERK and PI3K–AKT. Because these pathways are often upregulated in TNBC, we hypothesized that CIB1 may play a broader role in TNBC cell survival and tumor growth. Methods utilized include inducible RNAi depletion of CIB1 in vitro and in vivo, immunoblotting, clonogenic assay, flow cytometry, RNA-sequencing, bioinformatics analysis, and Kaplan–Meier survival analysis. CIB1 depletion resulted in significant cell death in 8 of 11 TNBC cell lines tested. Analysis of components related to PI3K–AKT and RAF–MEK–ERK signaling revealed that elevated AKT activation status and low PTEN expression were key predictors of sensitivity to CIB1 depletion. Furthermore, CIB1 knockdown caused dramatic shrinkage of MDA-MB-468 xenograft tumors in vivo. RNA sequence analysis also showed that CIB1 depletion in TNBC cells activates gene programs associated with decreased proliferation and increased cell death. CIB1 expression levels per se did not predict TNBC susceptibility to CIB1 depletion, and CIB1 mRNA expression levels did not associate with TNBC patient survival. Our data are consistent with the emerging theory of non-oncogene addiction, where a large subset of TNBCs depend on CIB1 for cell survival and tumor growth, independent of CIB1 expression levels. Our data establish CIB1 as a novel therapeutic target for TNBC.

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Section: Resultsmentioning

confidence: 99%

CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer

Black

Harrell

Leisner

et al. 2015

Breast Cancer Res Treat

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“…of adjacent normal tissue, and high-grade HCMV-LA was detected in only 3%, 11%, and 5%, Approximately 10-15% of BCs are classified as TNBC, for which treatment options are very limited 40 . Out of 10 TBNC cases in our study, 7 (70%) had high-grade expression of HCMV-IE.…”

Section: Discussionmentioning

confidence: 99%

Low Expression of Estrogen Receptor-α and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression

Rahbar

Touma

Costa

et al. 2017

Clinical Breast Cancer

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MicroAbstractThe mechanisms involved in initiation and progression of breast cancer (BC), the most common malignancy and second leading cause of cancer deaths in women, are largely unknown. Human cytomegalovirus (HCMV) has been detected in primary BC, sentinel lymph nodes and brain metastases of BC patients. We found HCMV DNA, RNA, and proteins in BC, and their prevalence was higher in advanced cancer. HCMV levels correlated inversely with estrogen (P = 0.02) and progesterone (p = 0.003) receptor expression. HER2 expression was also found to

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“…Critically, as elegantly discussed in several publications (2-4), these canine cancers, which bridge a gap between traditional rodent models and human clinical trials, can significantly speed up new anticancer drug development. For example, for drugs targeting the PI3K pathway (48) (Figure 7C), their efficacy, toxicity, dosage and schedule can be more accurately evaluated through clinical trials with canine patients, before entering human clinical trials. This will significantly reduce the cost and accelerate the drug discovery process.…”

Section: Discussionmentioning

confidence: 99%

Molecular Homology and Difference between Spontaneous Canine Mammary Cancer and Human Breast Cancer

et al. 2014

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Spontaneously occurring canine mammary cancer (MC) represents an excellent model of human breast cancer but is greatly understudied. To better utilize this valuable resource, we performed whole genome sequencing, whole exome sequencing, RNA-seq and/or high density arrays on 12 canine MC cases, including 7 simple carcinomas and four complex carcinomas. Canine simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many of which faithfully recapitulate key features of human breast cancer. Canine complex carcinomas, which are characterized by proliferation of both luminal and myoepithelial cells and are rare in human breast cancer, appear to lack genomic abnormalities. Instead, these tumors have about 35 chromatin-modification genes downregulated, and are abnormally enriched with active histone modification H4-acetylation while aberrantly depleted with repressive histone modification H3K9me3. Our findings indicate the likelihood that canine simple carcinomas arise from genomic aberrations whereas complex carcinomas originate from epigenomic alterations, reinforcing their unique value. Canine complex carcinomas offer an ideal system to study myoepithelial cells, the second major cell lineage of the mammary gland. Canine simple carcinomas, which faithfully represent human breast carcinomas at the molecular level, provide indispensable models for basic and translational breast cancer research.

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Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

Cited by 55 publications

References 59 publications

CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer

CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer

Low Expression of Estrogen Receptor-α and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression

Molecular Homology and Difference between Spontaneous Canine Mammary Cancer and Human Breast Cancer

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