Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

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A Novel Role for Cathepsin S as a Potential Biomarker in Triple Negative Breast Cancer

Journal of Oncology ◽

10.1155/2019/3980273 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Richard D. A. Wilkinson ◽

Roberta E. Burden ◽

Sara H. McDowell ◽

Darragh G. McArt ◽

Stephen McQuaid ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Dna Damage ◽

Adjuvant Therapy ◽

Dna Damage Repair ◽

Cathepsin S ◽

Damage Repair ◽

Potential Biomarker ◽

Repair Pathways ◽

Improved Outcome

Cathepsin S (CTSS) has previously been implicated in a number of cancer types, where it is associated with poor clinical features and outcome. To date, patient outcome in breast cancer has not been examined with respect to this protease. Here, we carried out immunohistochemical (IHC) staining of CTSS using a breast cancer tissue microarray in patients who received adjuvant therapy. We scored CTSS expression in the epithelial and stromal compartments and evaluated the association of CTSS expression with matched clinical outcome data. We observed differences in outcome based on CTSS expression, with stromal-derived CTSS expression correlating with a poor outcome and epithelial CTSS expression associated with an improved outcome. Further subtype characterisation revealed high epithelial CTSS expression in TNBC patients with improved outcome, which remained consistent across two independent TMA cohorts. Furtherin silicogene expression analysis, using both in-house and publicly available datasets, confirmed these observations and suggested high CTSS expression may also be beneficial to outcome in ER-/HER2+ cancer. Furthermore, high CTSS expression was associated with the BL1 Lehmann subgroup, which is characterised by defects in DNA damage repair pathways and correlates with improved outcome. Finally, analysis of matching IHC analysis reveals an increased M1 (tumour destructive) polarisation in macrophage in patients exhibiting high epithelial CTSS expression. In conclusion, our observations suggest epithelial CTSS expression may be prognostic of improved outcome in TNBC. Improved outcome observed with HER2+ at the gene expression level furthermore suggests CTSS may be prognostic of improved outcome in ER- cancers as a whole. Lastly, from the context of these patients receiving adjuvant therapy and as a result of its association with BL1 subgroup CTSS may be elevated in patients with defects in DNA damage repair pathways, indicating it may be predictive of tumour sensitivity to DNA damaging agents.

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Identification of Candidate Polymorphisms on Stress Oxidative and DNA Damage Repair Genes Related with Clinical Outcome in Breast Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms131216500 ◽

2012 ◽

Vol 13 (12) ◽

pp. 16500-16513 ◽

Cited By ~ 2

Author(s):

Patricia Rodrigues ◽

Jessica Furriol ◽

Begoña Bermejo ◽

Felipe Chaves ◽

Ana Lluch ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Clinical Outcome ◽

Cancer Patients ◽

Dna Damage Repair ◽

Breast Cancer Patients ◽

Damage Repair ◽

Stress Oxidative ◽

Repair Genes

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Association Between Polymorphisms in DNA Damage Repair Genes and Radiation Therapy–Induced Early Adverse Skin Reactions in a Breast Cancer Population: A Polygenic Risk Score Approach

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.12.021 ◽

2020 ◽

Vol 106 (5) ◽

pp. 948-957

Author(s):

Eunkyung Lee ◽

Sung Y. Eum ◽

Susan H. Slifer ◽

Eden R. Martin ◽

Cristiane Takita ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Radiation Therapy ◽

Risk Score ◽

Dna Damage Repair ◽

Polygenic Risk Score ◽

Skin Reactions ◽

Polygenic Risk ◽

Damage Repair ◽

Repair Genes

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Olaparib use in patients with metastatic breast cancer harboring somatic BRCA1/2 mutations or mutations in non-BRCA1/2, DNA damage repair genes

Clinical Breast Cancer ◽

10.1016/j.clbc.2021.12.007 ◽

2021 ◽

Author(s):

Elaine M Walsh ◽

Neha Mangini ◽

John Fetting ◽

Deborah Armstrong ◽

Isaac S Chan ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Metastatic Breast Cancer ◽

Dna Damage Repair ◽

Metastatic Breast ◽

Damage Repair ◽

Repair Genes

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FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair

Cell Death and Disease ◽

10.1038/s41419-021-04434-9 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Shu-Ping Wang ◽

Shi-Qi Wu ◽

Shi-Hui Huang ◽

Yi-Xuan Tang ◽

Liu-Qiong Meng ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Dna Damage ◽

Triple Negative Breast Cancer ◽

Cell Cycle Progression ◽

Triple Negative ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Cycle Progression ◽

Damage Repair

AbstractInducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

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