miRNAs as radio‐response biomarkers for breast cancer stem cells

Griñán‐Lisón, Carmen; Olivares-Urbano, María Auxiliadora; Jiménez, Gema; López‐Ruiz, Elena; Val, Coral del; Morata-Tarifa, Cynthia; Entrena, José Manuel; González-Ramírez, Amanda Rocío; Boulaiz, Houría; Herrera, M. Zurita; Núñez, María Isabel; Marchal, Juan Antonio

doi:10.1002/1878-0261.12635

Cited by 34 publications

(20 citation statements)

References 57 publications

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“… 27 Griñán-Lisón et al showed that miR-15b is tightly correlated with radio-resistance, stemness properties, and metastasis in BC, and could be applied as an attractive biomarker in the clinical arena, predominantly in radiotherapy so as to predict and monitor the tumor response to radiation. 28 However, whether miR-15b contributes to acquired endocrine resistance in BC and the potential mechanisms involved, remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

Wang

et al. 2021

DDDT

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Background: Paeoniflorin (Pae) possesses anti-tumor activity in various malignancies. However, it is unclear whether Pae plays a sensitizer role in breast cancer (BC) and the molecular mechanisms involved in this process. Our oligonucleotide microarray revealed that microRNA (miR)-15b is the most significantly downregulated miRNA in MCF-7/ 4-hydroxytamoxifen (4-OHT) cells treated with Pae. This paper summarized the relevance of Pae in BC cell endocrine resistance to tamoxifen (Tam) and the molecular mechanisms involved miR-15b expression. Materials and Methods: 4-OHT-resistant BC cell lines were developed and treated with different concentrations of Pae. Flow cytometry, lactose dehydrogenase activity, caspase-3 activity, colony formation, and EdU assays were carried out to assess the impact of Pae on BC cells. Differentially expressed miRNAs in BC cells treated with Pae were analyzed by microarray. Targeting mRNAs of screened miR-15b as well as the binding of forkhead box O1 (FOXO1) to the cyclin D1 (CCND1) promoter sequence were predicted through bioinformatics analysis. Finally, the expression of β-catenin signaling-related genes in cells was detected by Western blotting. Results: Pae (100 μg/mL) inhibited the clonality and viability of BC cells, while enhancing apoptosis in vitro. Pae also repressed miR-15b expression. Overexpression of miR-15b restored the growth and resistance of BC cells to 4-OHT. Moreover, Pae promoted FOXO1 expression by downregulating miR-15b, thereby transcriptionally inhibiting CCND1 and subsequently blocking β-catenin signaling. Conclusion: Pae inhibits 4-OHT resistance in BC cells by regulating the miR-15b/FOXO1/ CCND1/β-catenin pathway.

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Section: Discussionmentioning

confidence: 99%

Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

Wang

et al. 2021

DDDT

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“…miR-210 is highly radioresistant and overexpressed under hypoxic conditions [ 80 , 94 ]. Lastly, depending on the radiation dose delivered the expression of miRNAs varies in breast cancer and can be used as a biomarker in a personalized treatment [ 95 ].…”

Section: Molecular Mechanisms Involved In Cscs Radioresistancementioning

confidence: 99%

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

Olivares-Urbano

Griñán‐Lisón

Marchal

et al. 2020

Cells

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137

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Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial–mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

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“…Cancer stem cells (CSCs) are considered to contribute to radioresistance of tumors [5] due to several genetic and cellular adaptations, such as efficient DNA repair, hypoxia microenvironment and cell cycle blocked in the G0/G1-phase [6]. The expression of core pluripotency stem cell genes, including Homeobox Transcription Factor Nanog (NANOG), octamer-binding transcription factor 4 (OCT4) and sex determining region Y-box 2 (SOX2), play an important role in regulating selfrenewal and multi-lineage differentiation of cancer stem cells.…”

Section: Introductionmentioning

confidence: 99%

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer

Sun

Guo

et al. 2021

J Exp Clin Cancer Res

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Background Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. Methods In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients’ samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. Results ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. Conclusion Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.

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miRNAs as radio‐response biomarkers for breast cancer stem cells

Cited by 34 publications

References 57 publications

Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

Paeoniflorin Sensitizes Breast Cancer Cells to Tamoxifen by Downregulating microRNA-15b via the FOXO1/CCND1/β-Catenin Axis

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-β receptor II in breast cancer

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