Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

Background: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance.

Patients And Methods: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance.

KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control.

Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB zinc-finger proteins (KZNFs), but little is known about the regulation of ERVs in adult tissues. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function.

The HUSH complex cooperates with TRIM28 to repress young retrotransposons and new genes.

Retrotransposons encompass half of the human genome and contribute to the formation of heterochromatin, which provides nuclear structure and regulates gene expression. Here, we asked if the human silencing hub (HUSH) complex is necessary to silence retrotransposons and whether it collaborates with TRIM28 and the chromatin remodeler ATRX at specific genomic loci. We show that the HUSH complex contributes to de novo repression and DNA methylation of an SVA retrotransposon reporter.

Cancer cells, on your histone marks, get SETDB1, silence retrotransposons, and go!

Cancer cells thrive on genetic and epigenetic changes that confer a selective advantage but also need strategies to avoid immune recognition. In this issue, Cuellar et al. (2017.

Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes.

Receptor tyrosine kinases (RTKs) and integrins cooperate to stimulate cell migration and tumour metastasis. Here we report that an integrin influences signalling of an RTK, c-Met, from inside the cell, to promote anchorage-independent cell survival. Thus, c-Met and β1-integrin co-internalize and become progressively recruited on LC3B-positive 'autophagy-related endomembranes' (ARE).

Retrotransposons shape species-specific embryonic stem cell gene expression.

Over half of our genome is composed of retrotransposons, which are mobile elements that can readily amplify their copy number by replicating through an RNA intermediate. Most of these elements are no longer mobile but still contain regulatory sequences that can serve as promoters, enhancers or repressors for cellular genes. Despite dominating our genetic content, little is known about the precise functions of retrotransposons, which include both endogenous retroviruses (ERVs) and non-LTR elements like long interspersed nuclear element 1 (LINE-1).

Functional analysis of a breast cancer-associated FGFR2 single nucleotide polymorphism using zinc finger mediated genome editing.

Genome wide association studies have identified single nucleotide polymorphisms (SNP) within fibroblast growth factor receptor 2 (FGFR2) as one of the highest ranking risk alleles in terms of development of breast cancer. The potential effect of these SNPs, in intron two, was postulated to be due to the differential binding of cis-regulatory elements, such as transcription factors, since all the SNPs in linkage disequilibrium were located in a regulatory DNA region. A Runx2 binding site was reported to be functional only in the minor, disease associated allele of rs2981578, resulting in increased expression of FGFR2 in cancers from patients homozygous for that allele.

Fibroblast growth factor 22 is not essential for skin development and repair but plays a role in tumorigenesis.

Fibroblast Growth Factors play critical roles during development, tissue homeostasis and repair by controlling cell proliferation, survival, migration and differentiation. Of the 22 mammalian FGFs, FGF22, a member of the FGF7/10/22 subfamily, has been shown to have a clear role in synaptogenesis, but its roles in other tissues have not been studied. We have investigated the in vivo functions of FGF22 in mice.