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Purpose: Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM.Methods and Materials: Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with ≥5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined.Results: Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma.Conclusions: In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers. [ABSTRACT FROM AUTHOR]

Hypoxia is common in tumors and is associated with cancer progression and drug resistance, driven, at least in part, by genetic instability. Little is known on how hypoxia affects Translesion DNA Synthesis (TLS), in which error-prone DNA polymerases bypass lesions, thereby maintaining DNA continuity at the price of increased mutations. Here we show that under acute hypoxia, PCNA monoubiquitination, a key step in TLS, and expression of error-prone DNA polymerases increased under regulation of the HIF1α transcription factor. Knocking-down expression of DNA polymerase η, or using PCNA ubiquitination-resistant cells, inhibited genomic DNA replication specifically under hypoxia, and iPOND analysis revealed massive recruitment of TLS DNA polymerases to nascent DNA under hypoxia, uncovering a dramatic involvement of error-prone DNA polymerases in genomic replication. Of note, expression of TLS-polymerases correlates with VEGFA (primary HIF1α target) in a database of renal cell carcinoma, a cancer which accumulates HIF1α. Our results suggest that the tumor microenvironment can lead the cell to forgo, to some extent, the fast and accurate canonical DNA polymerases, for the more flexible and robust, but low-fidelity TLS DNA polymerases. This might endow cancer cells with resilience to overcome replication stress, and mutability to escape the immune system and chemotherapeutic drugs., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis., Competing Interests: The authors declare no conflict of interest