C/EBPδ demonstrates a dichotomous role in tumor initiation and promotion of epithelial carcinoma

AbstractC/EBPδ(CEBPD), a gene part of the highly conserved basic-leucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinoma of the ovary (HGSC). Overexpression ofC/EBPδin different tumors as glioblastoma and breast cancer either promotes tumor progression or inhibits growth. Despite these contradictory roles in different cancer types, we show thatC/EBPδoverexpression has a consistent function of downregulating proliferation and promoting migration in fallopian tube epithelial cells (FTE). We show that the FTE have both mesenchymal and epithelial cell characteristics. Further, our data supports a role forC/EBPδas an early regulatory transcriptional factor that promotes a mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating vimentin and N-cadherin in FTE cells. We demonstrate that overexpression ofC/EBPδin ovarian and breast cancer cell lines have consistent effects and phenotype as the FTE cells. Our findings suggest a role forC/EBPδin the early events of ovarian serous carcinogenesis which may be used to help further understand how the disease develops from a premalignant cells.

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CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials

eLife ◽

10.7554/elife.24179 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 53

Author(s):

Ann Lin ◽

Christopher J Giuliano ◽

Nicole M Sayles ◽

Jason M Sheltzer

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Cell Lines ◽

Cancer Cell ◽

Leucine Zipper ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines ◽

Chemotherapy Agent ◽

Basal Breast Cancer ◽

Cancer Types

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been reported to be a genetic dependency in several cancer types. MELK RNAi and small-molecule inhibitors of MELK block the proliferation of various cancer cell lines, and MELK knockdown has been described as particularly effective against the highly-aggressive basal/triple-negative subtype of breast cancer. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that mutagenizing MELK with CRISPR/Cas9 has no effect on the fitness of basal breast cancer cell lines or cell lines from six other cancer types. Cells that harbor null mutations in MELK exhibit wild-type doubling times, cytokinesis, and anchorage-independent growth. Furthermore, MELK-knockout lines remain sensitive to OTS167, suggesting that this drug blocks cell division through an off-target mechanism. In total, our results undermine the rationale for a series of current clinical trials and provide an experimental approach for the use of CRISPR/Cas9 in preclinical target validation that can be broadly applied.

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Educational Case: High-Grade Serous Carcinoma of the Ovary

Academic Pathology ◽

10.1177/23742895211032339 ◽

2021 ◽

Vol 8 ◽

pp. 237428952110323

Author(s):

Sophia Bunde ◽

Swikrity Upadhyay Baskota ◽

Jeffrey Fine ◽

Samer Khader

Keyword(s):

Organ System ◽

Learning Objectives ◽

National Standards ◽

Serous Carcinoma ◽

High Grade ◽

Full List ◽

Additional Information ◽

Disease Mechanisms ◽

Basic Competencies ◽

Carcinoma Of The Ovary

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040 .1

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BACH2 expression associates with survival in triple negative breast cancer.

10.31219/osf.io/7e52n ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Microarray Data ◽

Leucine Zipper ◽

Triple Negative ◽

Breast Cancer Patients ◽

Basic Leucine Zipper ◽

Primary Tumors ◽

Significant Gene

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of BTB and CNC homology 1, basic leucine zipper transcription factor 2, encoded by BACH2 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, BACH2 expression was correlated with overall survival in patients with breast cancer. BACH2 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

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Correlation of NFE2L2 mutation with higher tumor mutation burden (TMB), microsatellite instability (MSI) and PD-L1 expression in 3,716 cases of Chinese pan-cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16211 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16211-e16211

Author(s):

Bin Wu ◽

Aijun Li ◽

Keji Chen ◽

Lin Chen ◽

Qin Zhang ◽

...

Keyword(s):

Leucine Zipper ◽

Statistical Correlation ◽

Related Factor ◽

Chi Square ◽

Basic Leucine Zipper ◽

Poor Prognostic Factor ◽

Cancer Types ◽

The Difference ◽

Chi Square Analysis ◽

Pan Cancer

e16211 Background: Nuclear factor E2-related factor-2 (NFE2L2) gene encodes a transcription factor which is a member of basic leucine zipper (bZIP) proteins family. Overexpression of NFE2L2 lead to cell proliferation and promoted tumor metastasis. Previous report indicated that NFE2L2 mutation (NFE2L2-MT) was an independent poor prognostic factor in esophageal squamous cell carcinoma (ESCC). However, the correlation between NFE2L2 mutation and pan-cancer types of TMB, MSI, and PD-L1 expression is unclear. Methods: TMB analysis was performed in 3,716 Chinese pan-cancer patients who underwent NGS sequencing using a 539 gene panel. The TMB calculation included synonymous and nonsynonymous mutations and InDels. MSI analysis was performed in 3,110 patients. MSI-H was defined as above 10% positive of the 195 tested microsatellites sites. The PD-L1 expression analysis was performed in 3,415 patients with immunohistochemistry staining (IHC) by antibody SP263. PD-L1 positive was defined as greater than or equal to 1%. The statistical correlation was investigated using Chi-square analysis. TMB value was compared using Wilcoxon Rank Sum test. We used TCGA public database to verify the result. Results: The mutation frequency of NFE2L2 mutation was 2.66% (99/3716). The TOP 5 cancer types were liver cancer 3.53% (14/397), lung cancer 2.97% (42/1416), colorectal cancer 2.02% (7/347), gastric cancer 1.36% (3/221), soft tissue sarcoma 0.53% (1/189). NFE2L2-MT had a significant correlation with higher TMB (p = 2.2e-16), compared with NFE2L2 wild-type (NFE2L2-WT). Among 3110 samples with MSI status, the MSI-H percentage of NFE2L2-MT and NFE2L2-WT were 8.60% (8/93) and 1.33% (40/3017), respectively (p = 1.29e-7). In 3,415 patients with PD-L1 protein expression information, the PD-L1 positive percentage of NFE2L2-MT and NFE2L2-WT were 51.52% (51/99) and 61.9% (1,268/2,048), respectively. NFE2L2-WT has higher PD-L1 positive percentage than NFE2L2-MT (p = 0.01). NFE2L2-MT was significantly correlated with higher TMB and MSI when we used TCGA data to verify, p<0.0001. However, the survival analysis of 1661 MSKCC immunotherapy cohort showed that the median OS of NFE2L2-MT vs NFE2L2-WT was 21 months vs 18 months (p=0.858), but the difference was not significant. Conclusions: NFE2L2 mutation has a very significant correlation with higher TMB and MSI, but not related to PD-L1 expression. However, whether NFE2L2-MT is related to the efficacy of immunotherapy was still unclear and more clinical data were needed.

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Cytology positive pericardial effusion causing tamponade in patients with high grade serous carcinoma of the ovary

Gynecologic Oncology Reports ◽

10.1016/j.gore.2020.100621 ◽

2020 ◽

Vol 33 ◽

pp. 100621

Author(s):

Joni Kooy ◽

Rachelle Findley ◽

Gregg Nelson ◽

Pamela Chu

Keyword(s):

Pericardial Effusion ◽

Serous Carcinoma ◽

High Grade ◽

Carcinoma Of The Ovary

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Tumor core biopsies adequately represent immune microenvironment of high-grade serous carcinoma

Scientific Reports ◽

10.1038/s41598-019-53872-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Olivia D. Lara ◽

Santhoshi Krishnan ◽

Zhihui Wang ◽

Sara Corvigno ◽

YanPing Zhong ◽

...

Keyword(s):

Tissue Sample ◽

Serous Carcinoma ◽

Specific Cell ◽

High Grade ◽

Longitudinal Assessment ◽

Substantial Impact ◽

Major Interest ◽

Cancer Types ◽

Detection Of Biomarkers ◽

Cluster Of Differentiation

AbstractThe prognostic and therapeutic value of the tumor microenvironment (TME) in various cancer types is of major interest. Characterization of the TME often relies on a small representative tissue sample. However, the adequacy of such a sample for assessing components of the TME is not yet known. Here, we used immunohistochemical (IHC) staining and 7-color multiplex staining to evaluate CD8 (cluster of differentiation 8), CD68, PD-L1 (programmed death-ligand 1), CD34, FAP (fibroblast activation protein), and cytokeratin in 220 tissue cores from 26 high-grade serous ovarian cancer samples. Comparisons were drawn between a larger tumor specimen and smaller core biopsies based on number and location (central tumor vs. peripheral tumor) of biopsies. Our analysis found that the correlation between marker-specific cell subsets in larger tumor versus smaller core was stronger with two core biopsies and was not further strengthened with additional biopsies. Moreover, this correlation was consistently strong regardless of whether the biopsy was taken at the center or at the periphery of the original tumor sample. These findings could have a substantial impact on longitudinal assessment for detection of biomarkers in clinical trials.

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Transitional Cell Carcinoma of the Ovary is Related to High-grade Serous Carcinoma and is Distinct From Malignant Brenner Tumor

International Journal of Gynecological Pathology ◽

10.1097/pgp.0b013e31824d7445 ◽

2012 ◽

Vol 31 (6) ◽

pp. 499-506 ◽

Cited By ~ 41

Author(s):

Rola H. Ali ◽

Jeffrey D. Seidman ◽

Margaret Luk ◽

Steve Kalloger ◽

C. Blake Gilks

Keyword(s):

Transitional Cell Carcinoma ◽

Cell Carcinoma ◽

Transitional Cell ◽

Serous Carcinoma ◽

High Grade ◽

Brenner Tumor ◽

Carcinoma Of The Ovary

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Molecular identification of basal-like breast cancer through genomic analyses across five cancer types.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.1011 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 1011-1011

Author(s):

Aleix Prat ◽

Barbara Adamo ◽

Cheng Fan ◽

Maria Vidal ◽

Patricia Galvan ◽

...

Keyword(s):

Breast Cancer ◽

Squamous Cell ◽

Serous Carcinoma ◽

Colorectal Cancers ◽

Ovarian Cancers ◽

Different Types ◽

Basal Like Breast Cancer ◽

Cancer Types ◽

Tissue Of Origin ◽

Lung Adenocarcinomas

1011 Background: Common molecular alterations in different types of cancer are being identified and these might be successfully targeted regardless of the tumor´s tissue of origin. To better understand the genomic relationships among different types of cancer, we explored global gene expression patterns across breast, lung, ovarian, brain and colorectal cancers. Methods: A unified set of 1,707 samples of 5 human cancer types (breast [n=547], lung [squamous and adenocarcinomas, n=249], ovarian [serous carcinoma, n=489], brain [glioblastoma multiforme, n=202] and colorectal [n=220]) from The Cancer Genome Atlas (TCGA) project was evaluated. All microarrays were performed at the University of North Carolina under the same protocol and platform. All samples provided in each publication of TCGA were used, except for lung adenocarcinomas where we used TCGA public data. Consensus clustering was used to identify molecular entities, and breast cancer intrinsic subtyping was performed using the PAM50 predictor. Results: A total of 6 distinct and robust molecular entities were identified representing tumors from breast luminal/HER2-enriched, breast Basal-like, lung, ovarian, brain and colorectal cancers. Strikingly, 55%, 26%, 16% of Basal-like breast cancers were found to be more similar to squamous cell lung carcinomas, lung adenocarcinomas and ovarian cancers, respectively, compared to breast luminal/HER2-enriched tumors. Breast cancer intrinsic subtyping identified a Basal-like profile in 55% of squamous cell lung cancers, 53% of ovarian cancers and 8% of lung adenocarcinomas. Finally, single genes and gene signatures tracking cancer-related biological processes such as proliferation, angiogenesis and immune activation were found highly expressed in different proportions across the 6 molecular entities. Conclusions: These data suggest that breast tumors of the Basal-like subtype have a distinct cell of origin compared to luminal/HER2-enriched tumors. Clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer, squamous cell lung carcinoma and serous ovarian cancer.

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