Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol

Bernichon, Emilie; Vallard, Alexis; Wang, Q.; Attignon, Valéry; Pissaloux, Daniel; Bachelot, Thomas; Heudel, Pierre; Ray‐Coquard, Isabelle; Bonnet, Emmanuel; Fouchardière, Arnaud de la; Faure, C.; Chopin, Nicolás; Beurrier, F.; Racadot, S.; Sunyach, Marie‐Pierre; Rancoule, C.; Pérol, David; Corset, Véronique; Agrapart, Vincent; Tinquaut, Fabien; Blay, Jean‐Yves; Magné, Nicolas; Trédan, O.

doi:10.1093/annonc/mdx488

Cited by 26 publications

(23 citation statements)

References 17 publications

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“…The development of a radiation-resistant tumor cell population may be partly responsible for the disease recurrence experienced by 10-15% of patients with BC after breast-conserving strategy [14]. Therefore, improving radiosensitivity in BC FITC/PI, fluorescein isothiocyanate/propidium iodide; miR-93-5p inhibitor, hsa-miR-93-5p inhibitor; IR, ionizing radiation; miR-93-5p, hsa-miR-93-5p mimics; SD, standard deviation enhances the radiosensitivity of BC cells [17].…”

Section: Discussionmentioning

confidence: 99%

Investigation of miR-93-5p and its effect on the radiosensitivity of breast cancer

et al. 2021

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Accumulating evidence suggests that intrinsic resistance to radiotherapy reduces the survival of patients with cancer. The present study investigated whether miR-93-5p affects proliferation, migration, apoptosis, and radiosensitivity of breast cancer (BC) cells. MDA-MB-468, MCF-7, and MDA-MB-231 BC cells were incubated with hsa-miR-93-5p mimics, hsa-miR-93-5p inhibitor, and negative control RNA with or without exposure to ionizing radiation to determine cell proliferation, migration, and apoptosis using the Cell Counting Kit-8 assay, wound healing assay and apoptotic assay, respectively. Overexpression of miR-93-5p inhibited the migratory abilities (P = 0.001) and decreased the cell proliferation (P = 0.049) of MCF-7 cells. In MCF-7 cells, a significant increase in apoptosis was detected after treatment with miR-93-5p compared with the negative control (P = 0.001) and miR-93-5p inhibitor (P = 0.004). In MDA-MB-468 cells, the proportion of apoptotic cells increased following exposure to ionizing radiation (P = 0.001). The percentage of apoptotic MDA-MB-231 cells in the miR-93-5p group was significantly increase compared with that determined in the negative control (P = 0.044) and hsa-miR-93-5p inhibitor (P = 0.046) groups. In conclusion, our findings showed that miR-93-5p reduces BC cell proliferation and migratory capacity, and increases the ratio of apoptotic cells. Overexpression of miR-93-5p could increase radiosensitivity in BC cells by increasing apoptosis. This evidence provides new insight into the treatment of BC and identifies miR-93-5p as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Investigation of miR-93-5p and its effect on the radiosensitivity of breast cancer

et al. 2021

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“…The clinical significance of PIK3CA mutations in breast cancer remains complicated and controversial in literatures. Sobhani et al suggested that mutated PIK3CA represents an independent negative prognostic factor in breast cancer 48 ; while several studies indicated that mutations in PIK3CA were associated with favorable prognostic factor in unsorted breast cancer 49 – 52 . Notably, the detailed stratification of molecular subtypes in recent years has helped reduce controversy on the topic.…”

Section: Discussionmentioning

confidence: 99%

Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients

et al. 2018

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Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 (15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.

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“…Another study reported an increase in expression of genes involved in epithelial-to-mesenchymal (EMT) transition, angiogenesis, and proliferation in a highly radio-resistant tumor, glioblastoma [11]. Also, a study of genomic alterations in breast cancer patients revealed an association of phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation with loco-regional recurrence in case of breast cancer [12]. Thus, identification of specific radio-resistance-associated signature patterns can be of immense utility to develop novel treatment strategies or introduce "customized" radio-sensitizers to prevent recurrence [13].…”

Section: Introductionmentioning

confidence: 99%

Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells

et al. 2020

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Background: Poor-responsiveness of tumors to radiotherapy is a major clinical problem. Owing to the dynamic nature of the epigenome, the identification and targeting of potential epigenetic modifiers may be helpful to curb radio-resistance. This requires a detailed exploration of the epigenetic changes that occur during the acquirement of radio-resistance. Such an understanding can be applied for effective utilization of treatment adjuncts to enhance the efficacy of radiotherapy and reduce the incidence of tumor recurrence. Results: This study explored the epigenetic alterations that occur during the acquirement of radio-resistance. Sequential irradiation of MCF7 breast cancer cell line up to 20 Gy generated a radio-resistant model. Micrococcal nuclease digestion demonstrated the presence of compact chromatin architecture coupled with decreased levels of histone PTMs H3K9ac, H3K27 ac, and H3S10pK14ac in the G 0 /G 1 and mitotic cell cycle phases of the radio-resistant cells. Further investigation revealed that the radio-resistant population possessed high HDAC and low HAT activity, thus making them suitable candidates for HDAC inhibitor-based radio-sensitization. Treatment of radio-resistant cells with HDAC inhibitor valproic acid led to the retention of γH2AX and decreased H3S10p after irradiation. Additionally, an analysis of 38 human patient samples obtained from 8 different tumor types showed variable tumor HDAC activity, thus demonstrating inter-tumoral epigenetic heterogeneity in a patient population. Conclusion: The study revealed that an imbalance of HAT and HDAC activities led to the loss of site-specific histone acetylation and chromatin compaction as breast cancer cells acquired radio-resistance. Due to variation in the tumor HDAC activity among patients, our report suggests performing a prior assessment of the tumor epigenome to maximize the benefit of HDAC inhibitor-based radio-sensitization.

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Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol

Abstract: PIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity.

Cited by 26 publications

References 17 publications

Investigation of miR-93-5p and its effect on the radiosensitivity of breast cancer

Investigation of miR-93-5p and its effect on the radiosensitivity of breast cancer

Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients

Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells

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