Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer

Sinn, Bruno Valentin; Minckwitz, Gϋnter von; Denkert, Carsten; Eidtmann, Holger; Darb‐Esfahani, Silvia; Tesch, Hans; Kronenwett, Ralf; Hoffmann, G. M.; Belau, A.; Thommsen, C.; Holzhausen, H.-J.; Graßhoff, Sven-Thomas; Baumann, Klaus; Mehta, Keyur; Dietel, Manfred; Loibl, Sibylle

doi:10.1093/annonc/mdt162

Cited by 30 publications

(33 citation statements)

References 33 publications

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“…MUC-1 has been frequently described in breast cancer including subsets of HER2 + and triple-negative (TN) cases [26,27]. MUC-1 expression has been linked to trastuzumab resistance; however, targeting of MUC-1 may down-regulate HER2 activation and overcome the resistance in breast cancer cells [28].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast

et al. 2015

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast

et al. 2015

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“…In adenocarcinoma cells, which develop from such glandular epithelial cells, the expression of MUC1 is up-regulated and is expressed not only on the apical surface, but also on the entire cell surface. MUC1 overexpression is associated with a poor prognosis in several different types of carcinomas [2][3][4][5]; however, the exact mechanism underlying this association is unclear. One possible mechanism might be the involvement of MUC1 in immune escape of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Anti-KL-6/MUC1 monoclonal antibody reverses resistance to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity by capping MUC1

et al. 2019

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A B S T R A C TPolymorphic epithelial mucin (MUC1) is generally overexpressed on the surface of most adenocarcinomas including breast cancer. MUC1 is associated with chemotherapeutic resistance and immune evasion of cancer cells; however, the association between MUC1 and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) remains unclear. In this study, using six breast cancer cell lines with differing expression levels and MUC1 distribution, the present results show that cells with MUC1 overexpression and uniform surface distribution were resistant to trastuzumab-mediated ADCC. Importantly, trastuzumab resistance was reversed upon siRNA-mediated MUC1 knockdown and by using anti-KL-6/MUC1 monoclonal antibody (mAb). Additionally, we visually confirmed that anti-KL-6/MUC1 mAb induced capping of MUC1 molecules on the cell surface, resulting the in death of these cells. These results suggest that not only the quantity but also the cellsurface distribution of MUC1 affects the sensitivity of breast cancer cells to trastuzumab-mediated ADCC.

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“…In total, we identified 1776 genes that were differentially expressed between TC and TIL: 1003 genes were upregulated in TIL while 773 genes were upregulated in TC (Supplementary Tables 4 and 5). We observed that several genes such as MUC1, TFAP2A, MAL2 and ELF3 already reported to be expressed in breast cancer (14)(15)(16) and particularly TNBC (17), were among the most significantly highly expressed genes in microdissected TC compared to TIL (Supplementary table 4). In addition, TC expressed several epithelial markers like EPCAM, KRT8, KRT18 and KRT19.…”

Section: Differential Expression Analysismentioning

confidence: 86%

Spatial transcriptomics of tumor microenvironment in formalin-fixed paraffin-embedded breast cancer

Romanens

Chaskar

Tille

et al. 2020

Preprint

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Tumor samples are conserved in clinical practice in formalin-fixed paraffin-embedded (FFPE) blocks. Formalin fixation chemically alters nucleic acids, rendering transcriptomic analysis challenging. RNA-sequencing is usually performed on tumor bulk, without distinction of cell subtypes or location. Here we describe the development of a robust method for RNA extraction and exome-capture RNA-sequencing of lasercapture microdissected tumor cells (TC) and stromal immune cells (TIL) based on their morphology. We applied this method on 7 tumor samples (surgical or core needle biopsy) of triple-negative breast cancer (TNBC) stored in FFPE blocks over 3-10 years.Unsupervised clustering and principal component analysis showed a clear separation between gene-expression profile of TIL and TC. TIL were enriched in markers of B cells (CD79B, PAX5 and BLNK ) and T cells (CD2, CD3D and CD8B) whereas tumor cells expressed epithelial markers (EPCAM, MUC1 and KRT8). Microenvironment cell populations-counter (MCP)-counter deconvolution showed an enrichment in adaptive immune cell signatures in microdissected TIL. Transcripts of immune checkpoints were differentially expressed in TIL and TC. We further validated our results by qRT-PCR and multispectral immunohistochemistry. In conclusion, we showed that combining laser-capture microdissection and RNA-sequencing on archived FFPE blocks is feasible and allows spatial transcriptional characterization of tumor microenvironment.

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Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer

Cited by 30 publications

References 33 publications

Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast

Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast

Anti-KL-6/MUC1 monoclonal antibody reverses resistance to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity by capping MUC1

Spatial transcriptomics of tumor microenvironment in formalin-fixed paraffin-embedded breast cancer

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