Dataset Information

The frequency and clinical significance of DNA polymerase beta (POLβ) expression in breast ductal carcinoma in situ (DCIS).

ABSTRACT:

Background

The prediction of clinical behaviour of breast ductal carcinoma in situ (DCIS) and its progression to invasive disease remains a challenge. Alterations of DNA damage repair mechanisms are associated with invasive breast cancer (BC). This study aims to assess the role of base excision repair (BER) DNA Polymerase Beta (POLβ) in DCIS.

Methods

A cohort of DCIS comprising pure DCIS (n = 776) and DCIS coexisting with invasive BC (n = 239) were prepared as tissue microarrays. POLβ protein expression was assessed using immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Preclinically, we investigated the impact of POLβ depletion on stem cell markers in representative DCIS cell line models.

Results

Reduced POLβ expression was associated with aggressive DCIS features including high nuclear grade, comedo necrosis, larger tumour size, hormonal receptor negativity, HER2 overexpression and high Ki67 index. Combined low nuclear/low cytoplasmic POLβ expression showed the strongest association with the features' characteristics of aggressive behaviour. There was a gradual reduction in the POLβ expression from normal breast tissue, to DCIS, with the lowest expression observed in the invasive BC. Low POLβ expression was an independent predictor of recurrence in DCIS patients treated with breast conserving surgery (BCS). POLβ knockdown was associated with a significant increase in cell stemness markers including SOX2, NANOG and OCT4 levels in MCF10-DCIS cell lines.

Conclusion

Loss of POLβ in DCIS is associated with aggressive behaviour and it can predict recurrence. POLβ expression in DCIS provides an additional feature for patients' risk stratification for personalised therapy.

SUBMITTER: Al-Kawaz A

PROVIDER: S-EPMC8557137 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer where cells restricted to the ducts exhibit an atypical phenotype. Some DCIS lesions are believed to rapidly transit to invasive ductal carcinomas (IDCs), while others remain unchanged. Existing classification systems for DCIS fail to identify those lesions that transit to IDC. We studied gene expression patterns of 31 pure DCIS, 36 pure invasive cancers and 42 cases of mixed diagnosis (invasive cancer with an in situ component) using Agilent Whole Human Genome Oligo Microarrays 44k. Six normal breast tissue samples were also included as controls. qRT-PCR was used for validation. All DCIS and invasive samples could be classified into the intrinsic molecular subtypes defined for invasive breast cancer. Hierarchical clustering establishes that samples group by intrinsic subtype, and not by diagnosis. We observed heterogeneity in the transcriptomes among DCIS of high histological grade and identified a distinct subgroup containing seven of the 31 DCIS samples with gene expression characteristics more similar to advanced tumours. A set of genes independent of grade, ER-status and HER2-status was identified by logistic regression that univariately classified a sample as belonging to this distinct DCIS subgroup. qRT-PCR of single markers clearly separated this DCIS subgroup from the other DCIS, and contains samples from several histopathological and intrinsic molecular subtypes. The genes that differentiate between these two types of DCIS suggest several processes related to the re-organisation of the microenvironment. This raises interesting possibilities for identification of DCIS lesions both with and without invasive characteristics, which potentially could be used in clinical assessment of a woman's risk of progression, and lead to improved management that would avoid the current over- and under-treatment of patients. Breast cancer samples, 31 pure DCIS patients, 36 IDC patients, 42 mixed and 6 normal.

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