Somatic Mutation of PIK3CA (H1047R) Is a Common Driver Mutation Hotspot in Canine Mammary Tumors as Well as Human Breast Cancers

Breast cancer is one of the most frequently diagnosed cancers in both women and female dogs. Genome-wide association studies in human breast cancer (HBC) have identified hundreds of genetic variations and somatic driver mutations. However, only a handful of variants have been studied for rare HBC and their associations remain inconclusive. Spontaneous canine mammary tumor (CMT) is a great model for HBC, with clinical similarity. We thus performed whole-exome sequencing in 20 pairs of CMT and normal tissues in dogs. We newly found that PIK3CA was the most frequently mutated gene in CMT (45%). Furthermore, canine PIK3CA A3140G (H1047R), at what is known as the mutational hotspot of HBC, is also a hotspot in CMT. Targeted sequencing confirmed that 29% of CMTs had the same PIK3CA A3140G mutation. Integration of the transcriptome suggests that the PIK3CA (H1047R) induced cell metabolism and cell cycle via an increase of PCK2 and a decrease of CDKN1B but had no effect on cell apoptosis. We identified additional significantly mutated genes, including SCRN1 and CLHC1, which have not been reported in HBC. Our study recapitulated some known HBC-associated genes and human cancer signatures in CMT, and identified novel genes that may be relevant to HBC. This study may allow us to better understand both HBC and CMT and lend new insights into the development of biomarkers.

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Genomic assays in breast cancer: Issues yet to settle?

International Journal of Molecular and Immuno Oncology ◽

10.18203/issn.2456-3994.intjmolimmunooncol20164383 ◽

2016 ◽

Vol 1 (1) ◽

pp. 7

Author(s):

Maheboob M. Basade ◽

Vishwapriya M. Godkhindi

Keyword(s):

Breast Cancer ◽

Prediction Models ◽

Association Studies ◽

Late Recurrence ◽

Genome Wide Association Studies ◽

Single Individual ◽

Breast Cancers ◽

Genetic Profiling ◽

Genomic Assays ◽

Response To Chemotherapy

<p>Breast cancer today has emerged as the most commonly diagnosed malignancy in women world wide, accounting for 1 in 4 of every cancer diagnosed in women today. It is the leading cause of cancer death in women in the developing world and second leading cause of cancer (following lung cancer) in the developed world. Introduction of novel high through-output gene expression profiling technologies such as Next Generation Sequencing (NGS) and Genome wide association studies (GWAS) has led to the genetic profiling of breast cancer and to the development of genomic assays that ushered in an paradigm shift in the management of breast cancer from single individual variable to multivariate prediction models encompassing the tumors gross, microscopic and genetic variables. Oncotype DX, MammaPrint assay, MammoStrat assay, & Prosigna kit are some of the commercially available assays in various stages of validation. But various studies have reported discordance in risk stratification when the different tests is applied to the same patient cohort leading to a therapeutic quagmire. Tumor genetic signatures are not concordant but highly variable with each carrying its own unique set of genes dictating its growth, response to chemotherapy and risk of recurrence. Similarly triple negative breast cancers (TNBC), risk of late recurrence (> 5 years), validity of these over different population groups and quality control are some of the other issues which are yet to settle.</p>

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Effects of Glutamate and Aspartate on Prostate Cancer and Breast Cancer: A Mendelian Randomization Study

10.21203/rs.3.rs-744517/v1 ◽

2021 ◽

Author(s):

Lihong Zhang ◽

Yindan Lin ◽

Ze Yang ◽

Jingjia Li ◽

Yandi Sun ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Confidence Interval ◽

Mendelian Randomization ◽

Association Studies ◽

Underlying Mechanism ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Breast Cancers ◽

Early Assessment

Abstract Background: Respectively, prostate cancer and breast cancer are the second most and most commonly diagnosed cancer in men and woman, and they account for major cancer-related deaths world-wide. Special attention aiming to find potentially effective early detection of, and intervention strategies against, prostate cancer (PCa) and breast cancer need to be paid.Objective: Utilizing Mendelian randomization (MR), we aimed to estimate how genetically predicted glutamate and aspartate levels affected prostate and breast cancers development. Methods: Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to predict the serum levels of glutamate and aspartate from the publicly available genome-wide association studies (GWASs), which were conducted to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults and the glutamate and aspartate we chosen were two of 644 metabolites. The summary statistics for the largest and latest GWAS datasets for prostate cancer (61,106 controls and 79,148 cases) were from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and datasets for breast cancer (113,789 controls and 133,384 cases) were from Breast Cancer Association Consortium (BCAC). The analyses were performed through two-sample MR method. Results: Serum level of aspartate was positively associated with prostate cancer (Effect = 1.043; 95% confidence interval, 1.003 to 1.084; P = 0.034) and breast cancer (Effect = 1.033; 95% confidence interval, 1.004 to 1.063; P = 0.028); however, glutamate was neither associated with prostate cancer and breast cancer. The potential causal associations were robust to the sensitivity analysis.Conclusions: Our study found that the level of serum aspartate could serve as a risk factor that contributed to the development of prostate and breast cancers. Efforts detailing the underlying mechanism(s) would be extremely valuable in early assessment/diagnosis and strategizing clinical intervention of both cancers.

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Proteolytic Cleavage and Phosphorylation of a Tumor-associated ErbB4 Isoform Promote Ligand-independent Survival and Cancer Cell Growth

Molecular Biology of the Cell ◽

10.1091/mbc.e05-05-0402 ◽

2006 ◽

Vol 17 (1) ◽

pp. 67-79 ◽

Cited By ~ 80

Author(s):

Jorma A. Määttä ◽

Maria Sundvall ◽

Teemu T. Junttila ◽

Liisa Peri ◽

V. Jukka O. Laine ◽

...

Keyword(s):

Breast Cancer ◽

Kinase Activity ◽

Human Cancer ◽

Cellular Responses ◽

Breast Cancers ◽

Human Breast ◽

Cancer Cell Growth ◽

Single Receptor ◽

Erbb4 Receptor ◽

Ligand Stimulation

The ErbB1 and ErbB2 receptors are oncogenes with therapeutic significance in human cancer, whereas the transforming potential of the related ErbB4 receptor has remained controversial. Here, we have addressed whether four alternatively spliced ErbB4 isoforms differ in regulating cellular responses relevant for tumor growth. We show that the two tumor necrosis factor-α converting enzyme (TACE)-cleavable ErbB4 isoforms (the juxtamembrane [JM]-a isoforms) were overexpressed in a subset of primary human breast cancers together with TACE. The overexpression of the JM-a cytoplasmic (CYT)-2 ErbB4 isoform promoted ErbB4 phosphorylation, survival of interleukin-3-dependent cells, and proliferation of breast cancer cells even in the absence of ligand stimulation, whereas activation of the other three ErbB4 isoforms required ligand stimulation. Ligand-independent cellular responses to ErbB4 JM-a CYT-2 overexpression were regulated by both tyrosine kinase activity and a two-step proteolytic generation of an intracellular receptor fragment involving first a TACE-like proteinase, followed by γ-secretase activity. These data suggest a novel transforming mechanism for the ErbB4 receptor in human breast cancer that is 1) specific for a single receptor isoform and 2) depends on proteinase cleavage and kinase activity but not ligand activation of the receptor.

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NF2 inhibits proliferation and cancer stemness in breast cancer

Open Medicine ◽

10.1515/med-2020-0042 ◽

2020 ◽

Vol 15 (1) ◽

pp. 302-308

Author(s):

Zhibao Wang ◽

Zhiqiang Zhou ◽

Zhe Wang ◽

Yijie Cui

Keyword(s):

Breast Cancer ◽

Human Cancer ◽

Tumor Stage ◽

Clinicopathological Parameters ◽

Human Breast ◽

Cancer Stemness ◽

Normal Tissues ◽

Cancer Tissues ◽

Mcf 7

AbstractBackgroundPrevious studies have shown that NF2 plays a key role in tumorigenesis. NF2 has been illustrated to be downregulated in several types of human cancer. However, the role of NF2 in breast cancer remains unclear.MethodsWe used UALCAN and KM-plotter database to study NF2 expression in human breast cancer and corresponding normal tissues and analyzed its relationship with clinicopathological parameters. We investigated the role of NF2 in breast cancer cells behavior by inhibiting its expression in MDA-MB-231 and MCF-7 cells.ResultsIn this study, we found that NF2 was downregulated in breast cancer tissues compared to the adjacent normal tissues. We found that the low expression of NF2 was related with the tumor stage. NF2 overexpression inhibited the cell colon formation and stemness.ConclusionOur results indicate a role of NF2 in the progression of breast cancer.

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Design, Synthesis and Antitumor Assessment of Phenylureas Bearing 5-Fluoroindolin-2-one Moiety

Medicinal Chemistry ◽

10.2174/1573406416666200206123319 ◽

2020 ◽

Vol 16 (7) ◽

pp. 958-968

Author(s):

Yunrui Cai ◽

Tong Chen ◽

Huajian Zhu ◽

Hongbin Zou

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Human Cancer ◽

The Body ◽

Human Breast ◽

Design Synthesis ◽

Human Carcinoma ◽

Xenograft Models ◽

New Compounds ◽

Mcf 7

Background: The development of novel antineoplastic agents remains highly desirable. Objective: This study focuses on the design, synthesis, and antitumor evaluation of phenyl ureas bearing 5-fluoroindolin-2-one moiety. Methods: Three sets of phenylureas were designed and synthesized and their antiproliferative ability was measured against four human carcinoma cell lines (Hela, Eca-109, A549, and MCF-7) via MTT assay. In vivo anticancer activity was further evaluated in xenograft models of human breast cancer (MCF-7). Results: A total of twenty-one new compounds were synthesized and characterized by means of 1H and 13C NMR as well as HR-MS. Three sets of compounds (1a‒1c, 2a‒2c, and 3a‒3c) were initially constructed, and preliminary antiproliferative activities of these molecules were evaluated against Hela, Eca-109, A549 and MCF-7, highlighting the meta-substituted phenylureas (1a‒1c) as the most cytotoxic set. A series of meta-substituted phenylureas derivatives (1d‒1o) were then designed and synthesized for structure-activity relationship study. Most of the new compounds showed desirable cytotoxicity, among which compound 1g exhibited the most remarkable cytotoxic effects against the tested human cancer cells with IC50 values ranging from 1.47 to 6.79 μM. Further studies showed that compound 1g suppressed tumor growth in human breast cancer (MCF- 7) xenograft models without affecting the body weight of its recipients. Conclusion: In this study, twenty-one new compounds, containing the privileged structures of phenylurea and 5-fluoroindolin-2-one, were designed and synthesized. Subsequent structureactivity studies showed that 1g was the most bioactive antitumor agent among all tested compounds, hence a potentially promising lead compound once given further optimization.

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Mutation Mechanisms of Breast Cancer among the Female Population in China

Current Bioinformatics ◽

10.2174/1574893615666191220141548 ◽

2020 ◽

Vol 15 (3) ◽

pp. 253-259

Author(s):

Asmaa Amer ◽

Ahmed Nagah ◽

Tianhai Tian ◽

Xinan Zhang

Keyword(s):

Breast Cancer ◽

Gene Mutations ◽

Driver Mutations ◽

Human Breast ◽

Breast Epithelium ◽

Female Population ◽

Multistage Model ◽

The Usa ◽

Intermediate Cells ◽

Mutation Mechanisms

Background: Cancer is a genetic disease caused by the accumulation of gene mutations. It is important to derive the number of driver mutations that are needed for the development of human breast cancer, which may provide insights into the tumor diagnosis and therapy. Objective: This work is designed to investigate whether there is any difference for the mutation mechanism of breast cancer between the patients in the USA and those in China. We study the mechanisms of breast cancer development in China, and then compare these mechanisms with those in the USA. Methods: This work designed a multistage model including both gene mutation and clonal expansion of intermediate cells to fit the dataset of breast cancer in China from 2004 to 2009. Results: Our simulation results show that the maximum number of driver mutations for breast epithelium stem cells of females in China is 13 which is less than the 14 driver mutations of females in the USA. In addition, the two-hit model is the optimal one for the tumorigenesis of females in China, which is also different from the three-hit model that was predicted as the optimal model for the tumorigenesis of females in the USA. Conclusion: The differences of the mutation mechanisms between China and the USA reflect a variety of lifestyle, genetic influences, environmental exposure, and the availability of mammography screening.

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MicroRNAs as Biomarker for Breast Cancer

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200428113051 ◽

2020 ◽

Vol 20 (10) ◽

pp. 1597-1610 ◽

Cited By ~ 2

Author(s):

Taru Aggarwal ◽

Ridhima Wadhwa ◽

Riya Gupta ◽

Keshav Raj Paudel ◽

Trudi Collet ◽

...

Keyword(s):

Breast Cancer ◽

Association Studies ◽

Large Family ◽

Breast Cancer Diagnosis ◽

Cell Multiplication ◽

Cell Physiology ◽

Gene Transcript ◽

Genome Wide Association Studies ◽

Non Coding Rnas

Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.

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MRCKα Is Dispensable for Breast Cancer Development in the MMTV-PyMT Model

Cells ◽

10.3390/cells10040942 ◽

2021 ◽

Vol 10 (4) ◽

pp. 942

Author(s):

Mei Qi Kwa ◽

Rafael Brandao ◽

Trong H. Phung ◽

Jianfeng Ge ◽

Giuseppe Scieri ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression Signature ◽

Genomic Analysis ◽

Cancer Development ◽

Breast Cancer Cell Lines ◽

Normal Mammary Gland ◽

Breast Cancers ◽

Human Breast ◽

Breast Cancer Development

MRCKα is a ubiquitously expressed serine/threonine kinase involved in cell contraction and F-actin turnover, which is highly amplified in human breast cancer and part of a gene expression signature for bad prognosis. Nothing is known about the in vivo function of MRCKα. To explore MRCKα function in development and in breast cancer, we generated mice lacking a functional MRCKα gene. Mice were born close to the Mendelian ratio and showed no obvious phenotype including a normal mammary gland formation. Assessing breast cancer development using the transgenic MMTV-PyMT mouse model, loss of MRCKα did not affect tumor onset, tumor growth and metastasis formation. Deleting MRCKα and its related family member MRCKβ in two triple-negative breast cancer cell lines resulted in reduced invasion of MDA-MB-231 cells, but did not affect migration of 4T1 cells. Further genomic analysis of human breast cancers revealed that MRCKα is frequently co-amplified with the oncogenes ARID4B and AKT3 which might contribute to the prognostic value of MRCKα expression. Collectively, these data suggest that MRCKα might be a prognostic marker for breast cancer, but probably of limited functional importance.

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