• J. Am. Coll. Surg. · Jul 2020

    Breast Heterogeneity: Obstacles to Developing Universal Biomarkers of Breast Cancer Initiation and Progression.

    • Rebecca C Dirks, Heather N Burney, Manjushree Anjanappa, George E Sandusky, Yangyang Hao, Yunlong Liu, Max C Schmidt, and Harikrishna Nakshatri.
    • Departments of Surgery, Indianapolis, IN.
    • J. Am. Coll. Surg. 2020 Jul 1; 231 (1): 85-96.

    BackgroundPredicting outcomes and response to therapy through biomarkers is a major challenge in cancer research. In previous studies, we suggested that inappropriate "normal" tissue samples used for comparison with tumors, inter-individual heterogeneity in gene expression, and genetic ancestry all influence biomarker expression in tumors. The aim of this study was to investigate these factors in breast cancer using breast tissues from healthy women and normal tissue adjacent to tumor (NAT) with matrix metalloproteinase 7 (MMP7) as a candidate biomarker.Study DesignRNA sequencing was performed on primary luminal progenitor cells from healthy breast, NATs, and tumors to identify transcriptomes enriched in NATs and breast cancer. Expression of select genes was validated via quantitative reverse transcription polymerase chain reaction of RNA and via immunohistochemistry of a tissue microarray of normal, NAT, and tumor samples of different genetic ancestry.ResultsTwenty-six genes were significantly overexpressed in NATs and tumors compared with healthy controls at messenger RNA level and formed a para-inflammatory network. MMP7 had the greatest expression in tumor cells, with upregulation confirmed by quantitative reverse transcription polymerase chain reaction. Tumor-enriched but not NAT-enriched expression of MMP7 compared with healthy controls was reproduced at protein levels. When stratified by genetic ancestry, tumor-specific increase of MMP7 reached statistical significance in women of European ancestry.ConclusionsTranscriptome differences across healthy, NAT, and tumor tissue in breast cancer demonstrate an active para-inflammatory network in NATs and indicate unsuitability of NATs as "normal controls" in biomarker discovery. The discordance between transcriptomic and proteomic MMP7 expression in NATs and the influence of genetic ancestry on its protein expression highlight the complexity in developing universally acceptable biomarkers of breast cancer and the importance of genetic ancestry in biomarker development.Copyright © 2020 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

      Pubmed     Full text   Copy Citation     Plaintext  

      Add institutional full text...

    Notes

     
    Knowledge, pearl, summary or comment to share?
    300 characters remaining
    help        
    You can also include formatting, links, images and footnotes in your notes
    • Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.
    • Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.
    • Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.
    • Links can be included with: [my link to pubmed](http://pubmed.com)
    • Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")
    • For footnotes use [^1](This is a footnote.) inline.
    • Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..

    hide…