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The breasts
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
More recently, integration of information across a variety of platforms has highlighted the possibility of identifying more numerous and subtle groups of invasive breast cancer. Genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays may provide addition insights. As in DCIS, somatic mutations in three genes (TP53, PIK3CA, and GATA3) occur at >10% incidence across all breast cancers. Subtype-associated and novel gene mutations are described, however, including the enrichment of specific mutations in GATA3, PIK3CA, and MAP3K1 in luminal A cancers. Similarly, unsupervised analysis of paired DNA–RNA profiles has led to the identification of novel subgroups with distinct clinical outcomes including a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Such novel molecular stratifications of the breast cancer population provide insights and may lead to therapeutic options. For example, comparison of basal-like breast tumours with high-grade serous ovarian tumours shows molecular commonalities, possibly indicating a related aetiology and therapeutic options for these breast cancers with otherwise limited treatment choices.
Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
Sox9 can trigger the expression of its downstream targets, FGF9 and PGDS (prostaglandin D synthase) (40). Both FGF9 and PGDS promote the proliferation and differentiation of the Sertoli cells, thus promoting the masculinization of the testis (40). A shift of balance from Sox9/FGF9 to Wnt/β-catenin signaling can result in a transition from male to female in various species (44,45). In-frame missense and splicing mutations in the MAP kinase pathway gene MAP3K1 tilt the balance from the male to the female sex-determining pathway, resulting in the 46,XY disorder of sex development. These MAP3K1 mutations arbitrate this balance by enhancing the β-catenin activity and WNT/β-catenin/FOXL2 expression and by reducing the expression of SOX9/FGF9/FGFR2/SRY (46). In summary, Wnt signaling plays a major inhibitory role in testis determination.
Pathology of breast cancer metastasis and a view of metastasis to the brain
Published in International Journal of Neuroscience, 2023
Md Sakibuzzaman, Shahriar Mahmud, Tanzina Afroze, Sawsan Fathma, Ummul Barakat Zakia, Sabrina Afroz, Farzina Zafar, Maksuda Hossain, Amit Barua, Sabiha Akter, Hasanul Islam Chowdhury, Eram Ahsan, Shayet Hossain Eshan, Tasnuva Tarannum Fariza
Mutations also play a pivotal role in metastasis heterogeneity [16] and lead to therapeutic resistance [17]. Mutations in cellular tumor antigen P53, PIK3CA, PTEN, GATA3, and MAP3K1 can lead to breast tumors. Cellular tumor antigen P53 is most commonly mutated in TN and HER2-enriched subtypes but to a lesser extent mutated in luminal subtypes. Mutated PIK3CA is most common in luminal subtypes, but to a lesser extent mutated in TN and HER2-enriched subtypes [16]. Mutations in P53 and PIK3CA are drivers of primary breast tumors in brain metastasis [18]. ER+/HER2− breast cancer metastasis frequently possesses more genomic alterations than ER+/HER2− primary breast cancer [19]. Bertucci et al. have demonstrated that metastatic cells of a distant organ from the primary tumor possess the same genetic alterations to adapt and grow in the host microenvironment [20]. Further research is needed to clarify whether the high prevalence of specific mutations enhances metastatic propensity in particular subtypes of primary breast cancer.
Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: a novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade
Published in Drug and Chemical Toxicology, 2022
Rania M. Salama, Merihane M. Nasr, Jannatullah I. Abdelhakeem, Omar K. Roshdy, Mohamed A. ElGamal
An RNeasy Kit (Qiagen, Hilden, Germany) was used to extract the total RNA from the kidney tissue homogenate. First, centrifugation of the renal tissue lysate was done for 3 minutes at 10,000 × g, then the supernatant was separated. Next, reverse transcription of the supernatant into complementary DNA was performed according to the procedures of High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, CA). Lastly, MAP3K1 and SMAD3 gene expression was assessed by SYBR® Green PCR Master Mix (Applied Biosystems, CA) according to the written protocol. The ΔΔ CT method was used to estimate the relative expression of the target genes as formerly explained (Livak and Schmittgen 2001), and they were normalized against GAPDH, the housekeeping gene. The primers sequence and GenBank accession number for MAP3K1 (Gross et al.2009), SMAD3 (Zhao et al.2020) and GADPH genes are shown in Table 2.
Genetic associations of T cell cancer immune response with tumor aggressiveness in localized prostate cancer patients and disease reclassification in an active surveillance cohort
Published in OncoImmunology, 2019
Qinchuan Wang, Justin R. Gregg, Jian Gu, Yuanqing Ye, David W. Chang, John W. Davis, Timothy C. Thompson, Jeri Kim, Christopher J. Logothetis, Xifeng Wu
To further investigate potential mechanisms through which identified SNPs may increase the risk of PCa aggressiveness, we performed functional characterization studies in silico. We assessed somatic mRNA expression for genes related to SNPs present in the UFG analysis, leveraging The Cancer Genome Atlas (TCGA) data involving 499 prostate tumors and 52 normal tissue samples. The analysis revealed the expression of MAP3K1, PIK3R1, NFATC2 and RHOA were significantly down-regulated in tumor samples, whereas that of CASP8, PSMD11, TRAF2 and PSMD3 were significantly up-regulated in tumors (P < 0.01 in all cases; Figure S1). No differences were found for PSMB8, CD48, NFATC1 and ITGAL genes (Figure S1). Additionally, no significant expression quantitative trait loci (eQTL) associations were observed in prostate tissues from the Genotype-Tissue Expression (GTEx) database.