ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen

ATM遺伝子変異による乳癌発症機構を解明 --HBOC症候群の乳腺特異的発癌機構の解明に貢献--. 京都大学プレスリリース. 2023-02-09.ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis

A study on prevention of bleeding complications using lusutrombopag for safe RFA in patients with hepatocellular carcinoma with low platelet counts: prospective observational study

Abstract Background Platelet (PLT) transfusion was the most practical way to increase patients’ PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. Methods Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts ( 50,000 PLT µL− 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL− 1 but > 50,000 µL− 1. Conclusions Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. Trial registration This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022)

Activity of IHE-Japan - Current status and Future -

The IHE-Japan has been active from July 2001. IHE-J consists of the several committees. The Japanese connectathon was held since February 2004. The number of the participant of the con-nectathon is increasing. The IHE-J demonstrated the integration profile at the academic assembly yearly. We made the promotion DVD yearly, and several workshops for education. In Japan, the implementations of the IHE based system were reported at four hospitals. We believe that many hospitals will profit from IHE in future.EuroPACS　200

TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double‐strand breaks (DSBs), where TOP2 homodimers covalently bind to 5′ DSB ends, called TOP2‐DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase‐2 (TDP2) removes 5′ TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0/G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0/G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen‐induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2‐deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.This work was conducted through the Joint Research Program of the Radiation Biology Center, Kyoto University and supported by the following grants: a Grant‐in‐Aid from the Ministry of Education, Science, Sport and Culture to S.T. (KAKENHI 25650006, 23221005 and 16H06306) and H.S. (KAKENHI 16H02953, 18H04900 and 19H04267), the Takeda Research Foundation, and Mitsubishi Foundation (to H.S.) and JSPS Core‐to‐Core Program, A. Advanced Research Networks (to S.T.), and Andalusian Government grants SAF2010‐21017, SAF2013‐47343‐P, SAF2014‐55532‐R, CVI‐7948 and FEDER funds (to F.C.‐L.).Peer reviewe