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1.
Recombinant human erythropoietin alters gene expression and stimulates proliferation of MCF-7 breast cancer cells
Nina Trošt, Tina Stepišnik, Sabina Berne, Anja Pucer Janež, Toni Petan, Radovan Komel, Nataša Debeljak, 2013, published scientific conference contribution

Abstract: Background. Functional erythropoietin (EPO) signaling is not specific only to erythroid lineages and has been confirmed in several solid tumors, including breast. Three different isoforms of erythropoietin receptor (EPOR) have been reported, the soluble (EPOR-S) and truncated (EPOR-T) forms acting antagonistically to the functional EPOR. In this study, we investigated the effect of human recombinant erythropoietin (rHuEPO) on cell proliferation, early gene response and the expression of EPOR isoforms in the MCF-7 breast cancer cell line.Materials and methods. The MCF-7 cells were cultured with or without rHuEPO for 72 h or 10 weeks and assessed for their growth characteristics, expression of early response genes and different EPOR isoforms. The expression profile of EPOR and EPOR-T was determined in a range of breast cancer cell lines and compared with their invasive properties.Results. MCF-7 cell proliferation after rHuEPO treatment was dependent on the time of treatment and the concentration used. High rHuEPO concentrations (40 U/ml) stimulated cell proliferation independently of a preceding long-term exposure of MCF-7 cells to rHuEPO, while lower concentrations increased MCF-7 proliferation only after 10 weeks of treatment. Gene expression analysis showed activation of EGR1 and FOS, confirming the functionality of EPOR. rHuEPO treatment also slightly increased the expression of the functional EPOR isoform, which, however, persisted throughout the 10 weeks of treatment. The expression levels of EPOR-T were not influenced. There were no correlations between EPOR expression and the invasiveness of MCF-7, MDA-MB-231, Hs578T, Hs578Bst, SKBR3, T-47D and MCF-10A cell lines.Conclusions. rHuEPO modulates MCF-7 cell proliferation in time- and concentration-dependent manner. We confirmed EGR1, FOS and EPOR as transcription targets of the EPO-EPOR signaling loop, but could not correlate the expression of different EPOR isoforms with the invasiveness of breast cancer cell lines.
Keywords: breast cancer, erythropoietin, gene expression
Published in DiRROS: 22.03.2024; Views: 49; Downloads: 24
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2.
Contrasting effect of recombinant human erythropoietin on breast cancer cell response to cisplatin induced cytotoxicity
Nina Trošt, Peter Juvan, Gregor Serša, Nataša Debeljak, 2012, original scientific article

Abstract: Background. Human recombinant erythropoietin (rHuEpo) that is used for the treatment of the chemotherapy-induced anaemia in cancer patients was shown to cause detrimental effects on the course of disease due to increased adverse events inflicting patient's survival, potentially related to rHuEpo-induced cancer progression. In this study, we elucidate the effect of rHuEpo administration on breast cancer cell proliferation and gene expression after cisplatin (cDDP) induced cytotoxicity. Materials and methods. Two breast carcinoma models, MCF-7 and MDA-MB-231 cell lines, were used differing in oestrogen (ER) and progesterone (PR) receptors and p53 status. Cells wer e cultured with or without rHuEpo for 24 h or 9 weeks and their growth characteristics after cDDP treatment were assessed together with expression ofgenes involved in the p53-signaling pathway. Results. Short-term exposure ofbreast cancer cells to rHuEpo lowers their proliferation and reduces cDDP cytotoxic potency. In contrast, long-term exposure of MCF-7 cells to rHuEpo increases proliferation and predisposes MCF-7 cells to cDDP cytotoxicity, but has no effect on MDA-MB-231 cells. MDA-MB-231 cells show altered level of ERK phosphorylation, indicating involvement of MAPK signalling pathway. Gene expression analysis of p53-dependent genes and bcl-2 gene family members confirmed differences between long and short-term rHuEpo effects, indicating the most prominent changes in BCL2 and BAD expression. Conclusions. Proliferation and survival characteristics of MCF-7 cells are reversely modulated by the length of the rHuEpo exposure. On the other hand, MDA-MB-231 cells are almost irresponsive to long-term rHuEpo, supposedly due to the mutated p53 and ER(+)/PR(-) status. The p53 and ER/PR status may predict tumour response on rHuEpo and cDDP treatment.
Keywords: breast cancer, erythropoietin, cisplatin, cytotoxicity
Published in DiRROS: 22.03.2024; Views: 38; Downloads: 17
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3.
Breast cancer risk prediction using Tyrer-Cuzick algorithm with an 18-SNPs polygenic risk score in a European population with below-average breast cancer incidence
Tjaša Oblak, Petra Škerl, Benjamin J. Narang, Rok Blagus, Mateja Krajc, Srdjan Novaković, Janez Žgajnar, 2023, original scientific article

Abstract: Goals: To determine whether an 18 single nucleotide polymorphisms (SNPs) polygenic risk score (PRS18) improves breast cancer (BC) risk prediction for women at above-average risk of BC, aged 40-49, in a Central European population with BC incidence below EU average. Methods: 502 women aged 40-49 years at the time of BC diagnosis completed a questionnaire on BC risk factors (as per Tyrer-Cuzick algorithm) with data known at age 40 and before BC diagnosis. Blood samples were collected for DNA isolation. 250 DNA samples from healthy women aged 50 served as a control cohort. 18 BC-associated SNPs were genotyped in both groups and PRS18 was calculated. The predictive power of PRS18 to detect BC was evaluated using a ROC curve. 10-year BC risk was calculated using the Tyrer-Cuzick algorithm adapted to the Slovenian incidence rate (S-IBIS): first based on questionnaire-based risk factors and, second, including PRS18. Results: The AUC for PRS18 was 0.613 (95 % CI 0.570-0.657). 83.3 % of women were classified at above-average risk for BC with S-IBIS without PRS18 and 80.7 % when PRS18 was included. Conclusion: BC risk prediction models and SNPs panels should not be automatically used in clinical practice in different populations without prior population-based validation. In our population the addition of an 18SNPs PRS to questionnaire-based risk factors in the Tyrer-Cuzick algorithm in general did not improve BC risk stratification, however, some improvements were observed at higher BC risk scores and could be valuable in distinguishing women at intermediate and high risk of BC.
Keywords: early breast cancer, polygenic risk score, risk prediction
Published in DiRROS: 21.03.2024; Views: 57; Downloads: 21
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4.
Trends and timing of risk-reducing mastectomy uptake in unaffected BRCA1 and BRCA2 carriers in Slovenia
Taja Ložar, Janez Žgajnar, Andraž Perhavec, Ana Blatnik, Srdjan Novaković, Mateja Krajc, 2021, original scientific article

Abstract: Objectives. Risk-reducing mastectomy (RRM) is one of key prevention strategies in female carriers of germline BRCA pathogenic/likely pathogenic variants (PV/LPV). We retrospectively investigated the rate, timing and longitudinal trends of bilateral RRM uptake and the incidence and types of cancers among unaffected BRCA carriers who underwent genetic counseling at the Institute of Oncology Ljubljana in Slovenia. Materials and Methods. Female BRCA carriers without personal history of cancer were included in the study. Clinical data on PV/LPV type, date of RRM, type of reconstructive procedure, occult carcinoma and histopathology results was collected and analyzed. Results. Of the 346 unaffected BRCA carriers (median age 43 years, 70% BRCA1, 30% BRCA2, median follow-up 46 months) who underwent genetic testing between October 1999 and December 2019, 25.1% had a RRM (range 35-50 years, median age at surgery 38 years). A significant difference in time to prophylactic surgery between women undergoing RRM only vs. women undergoing RRM combined with risk-reducing salpingo-oophorectomy was observed (22.6 vs 8.7 months, p=0.0009). We observed an upward trend in the annual uptake in line with the previously observed Angelina Jolie effect. In 5.7% of cases, occult breast cancer was detected. No women developed breast cancer after RRM. Women who did not opt for surgical prevention developed BRCA1/2-related cancers (9.3%). Conclusion. The uptake of RRM among unaffected BRCA carriers is 25.1% and is similar to our neighboring countries. No women developed breast cancer after RRM while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. The reported data may provide meaningful aid for carriers when deciding on an optimal prevention strategy.
Keywords: risk-reducing mastectomy, breast cancer, BRCA
Published in DiRROS: 21.09.2022; Views: 410; Downloads: 139
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5.
PARP inhibitor olaparib has a potential to increase the effectiveness of electrochemotherapy in BRCA1 mutated breast cancer in mice
Maša Omerzel, Tanja Jesenko, Boštjan Markelc, Larisa Janžič, Maja Čemažar, Gregor Serša, 2021, original scientific article

Abstract: Electrochemotherapy (ECT), a local therapy, has different effectiveness among tumor types. In breast can-cer, its effectiveness is low; therefore, combined therapies are needed. The aim of our study was to com-bine ECT with PARP inhibitor olaparib, which could inhibit the repair of bleomycin or cisplatin inducedDNA damage and potentiate the effectiveness of ECT. The effects of combined therapy were studied inBRCA1mutated (HCC1937) and non-mutated (HCC1143) triple negative breast cancer cell lines.Therapeutic effectiveness was studied in 2D and 3D cell cultures andin vivoon subcutaneousHCC1937 tumor model in mice. The underlying mechanism of combined therapy was determined withthe evaluation ofcH2AX foci. Combined therapy of ECT with bleomycin and olaparib potentiated theeffectiveness of ECT inBRCA1mutated HCC1937, but not in non-mutated HCC1143 cells. The combinedtherapy had a synergistic effect, which was due to the increased number of DNA double strand breaks.Addition of olaparib to ECT with bleomycinin vivoin HCC1937 tumor model had only minimal effect,indicating repetitive olaparib treatment would be needed. This study demonstrates that DNA repar inhibiting drugs, like olaparib, have the potential to increase the effectiveness of ECT with bleomycin.
Keywords: electrochemotherapy, breast cancer, olaparib, bleomycin
Published in DiRROS: 21.09.2022; Views: 493; Downloads: 169
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6.
BAP1-defficient breast cancer in a patient with BAP1 cancer syndrome
Ana Blatnik, Domen Ribnikar, Vita Šetrajčič Dragoš, Srdjan Novaković, Vida Stegel, Biljana Grčar-Kuzmanov, Nina Boc, Barbara Perić, Petra Škerl, Gašper Klančar, Mateja Krajc, 2022, original scientific article

Abstract: BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.
Keywords: BAP1, breast cancer, hereditary cancer syndromes, immunotherapy
Published in DiRROS: 19.09.2022; Views: 427; Downloads: 175
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7.
Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling : a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials
2019, original scientific article

Abstract: Background: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37,298 (93%) of 40,070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28.0% vs 31.4%; RR 0.86, 95% CI 0.82-0.89; p<0.0001). 10-year breast cancer mortality was similarly reduced (18.9% vs 21.3%; RR 0.87, 95% CI 0.83-0.92; p<0.0001), as was all-cause mortality (22.1% vs 24.8%; RR 0.87, 95% CI 0.83-0.91; p<0.0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4.1% vs 4.6%; RR 0.88, 95% CI 0.78-0.99; p=0.034). Recurrence reductions were similar in the seven trials (n=10,004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24.0% vs 28.3%; RR 0.83, 95% CI 0.76-0.91; p<0.0001), in the six trials (n=11,028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28.1% vs 31.3%; RR 0.87, 95% CI 0.80-0.94; p=0.0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30.4% vs 35.0%; RR 0.82, 95% CI 0.74-0.90; p<0.0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0.0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation: Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.
Keywords: breast neoplasms, women, drug therapy, clinical protocols, meta-analysis, breast cancer, chemotherapy, treatment schedule, randomized trials
Published in DiRROS: 22.10.2020; Views: 1262; Downloads: 1069
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