Mouse mammary tumor virus (MMTV) is a well-known cause of mammary tumors in mice transmitted as endogenous proviruses or exogenously as infectious virions. The hypothesis that a retrovirus homologous to MMTV is involved in human breast cancers has resulted in renewed interest in the etiology of human breast cancer. Therefore, the detection of MMTV-like exogenous sequences in 30-40 % of invasive breast cancer has increased attention towards this hypothesis. To detect the prevalence of MMTV in Pakistani population, 666-bp-long MMTV envelop and 630-bp LTR sequences were amplified from breast cancer patient samples (tissue biopsies and peripheral blood) using mouse with mammary tumor as control. MMTV-like virus env and LTR DNA sequences were detected in 20 and 26 % of breast tumor samples, respectively, from the total of 80 breast cancer patients' blood and tissue samples. No significant association was observed between age, grade of disease, and lymph node involvement with the prevalence of MMTV-like sequences. Our data add to the growing number of studies implicating MMTV-like virus in human breast cancer, but still clear causal association of MMTV to breast cancer remains to be reputable.
High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib.
IntroductionConstitutive expression of interferons (IFNs) and their downstream signalling pathways play a critical role in host responses to cell transformation in the tumour microenvironment. Induction of IFNs initiates the transcription of a variety of genes, so called IFN- stimulated genes (ISGs). Although expression of ISGs is classically associated with tumour suppression, a subset defined as the IRDS (Interferon - Related DNA- Damage Resistance Signature), is elevated in response to endogenous IFN, self-DNA and RNA exposure in the tumour microenvironment acquiring radiation and chemotherapy resistance. INF induced transmembrane receptor (IFITM1) is thought to participate in proliferating signalling and oncogenesis. Three out of five IFITM genes (IFITM1,2,3) share high amino-acid homology, however, IFITM1 has a unique C-terminal domain, a 13 amino-acid extension, and a shorter N-terminal amino-acid sequence.Material and methodsTo analyse the impact of IFITM1 loss, or mutation, on signalling and phenotypic events such as growth, viability and drug resistance, knock – out, knock – in and domain mutants were generated using Crispr/Cas9 mediated gene – editing. To identify the effects of radiation in the growth of wild type and mutant IFITM1 cells, proliferation assays were conducted while immunoassays were used to check for activation of the IRDS pathway. The gene edited cell lines were used in Mass Spectrometry proteomic approaches to discover IFITM1 interacting proteins under normal growth conditions as well as in INF treated and/or radiated cells.Results and discussionsIrradiation of glioma stem cells, results in a substantial increase in the expression of IFITM1 and an activation of the IRDS pathway which suggests a potential mechanism by which cancer stem cells escape chemotherapy. Deletion of IFITM1 in SiHa cells results in sensitivity to chemo- and radiation therapy, while loss of both IFITM1 and IFITM3 function generates chemoresistant cancer cells suggesting a potential interaction between IFITM1 and IFITM3.Structure-function analysis has shown that the C-terminal regulatory domain of IFITM1 is required for its ability to promote cell growth and to localise to the membrane.ConclusionWe have identified IFITM1 as an upstream regulator of the IRDS which promotes cancer cell survival and mediates chemoresistance. The C-terminal domain of IFITM1 is important for its proliferative activity in cancer and lay the foundation for future research aiming to determine IFITM1’s potential as a therapeutic target in cancer.
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