Abstract 2521: Race specific differences in DNA damage repair dysregulation in breast cancer and association with 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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Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15555794826018 ◽

2020 ◽

Vol 28 (1) ◽

pp. 33-40 ◽

Cited By ~ 3

Author(s):

Annemarie E. M. Post ◽

Johan Bussink ◽

Fred C. G. J. Sweep ◽

Paul N. Span

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cross Resistance ◽

Damage Repair ◽

Breast Cancer Cohort ◽

Tamoxifen Resistant ◽

Repair Genes

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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Studies on DNA Damage Repair and Precision Radiotherapy for Breast Cancer

Advances in Experimental Medicine and Biology - Translational Research in Breast Cancer ◽

10.1007/978-981-10-6020-5_5 ◽

2017 ◽

pp. 105-123 ◽

Cited By ~ 2

Author(s):

Yanhui Jiang ◽

Yimin Liu ◽

Hai Hu

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Dna Damage Repair ◽

Damage Repair ◽

Precision Radiotherapy

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Abstract P3-11-12: Biomarker phase neo-DDRD trial: Predicting response to neoadjuvant chemotherapy (NAC) in early breast cancer using the DNA damage repair deficiency (DDRD) assay

10.1158/1538-7445.sabcs18-p3-11-12 ◽

2019 ◽

Author(s):

EE Parkes ◽

CR James ◽

T Lioe ◽

S Walker ◽

KI Savage ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Neoadjuvant Chemotherapy ◽

Early Breast Cancer ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Deficiency ◽

Response To Neoadjuvant Chemotherapy

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A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer

10.1101/281196 ◽

2018 ◽

Author(s):

Laura A. Baker ◽

Christoph Krisp ◽

Daniel Roden ◽

Holly Holliday ◽

Sunny Z. Wu ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Dna Damage Repair ◽

Chemotherapy Resistance ◽

Clinical Analysis ◽

Damage Repair ◽

Damage Response ◽

Basal Like Breast Cancer ◽

Dna Damage Signalling

AbstractBasal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Here, we have defined a molecular mechanism of action for ID4 in BLBC and the related disease highgrade serous ovarian cancer (HGSOV), by combining RIME proteomic analysis and ChIP-Seq mapping of genomic binding sites. Remarkably, these studies have revealed novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage and regulating DNA damage signalling. Clinical analysis demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair pathways. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOV.

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