Contrasting roles of different mismatch repair proteins in basal-like breast cancer

Jiao Mo; Nicholas Borcherding; Sung Jo; Tanzia Islam Tithi; Kailey E Cash; Masayoshi Honda; Lei Wang; Kawther K. Ahmed; Ronald Weigel; Maria Spies; Ryan Kolb; Weizhou Zhang

doi:10.1101/2023.07.20.549745

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Contrasting roles of different mismatch repair proteins in basal-like breast cancer

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Contrasting roles of different mismatch repair proteins in basal-like breast cancer

Jiao Mo, Nicholas Borcherding, Sung Jo, Tanzia Islam Tithi, Kailey E Cash, Masayoshi Honda, Lei Wang, Kawther K. Ahmed, Ronald Weigel, Maria Spies, …

bioRxiv

Cold Spring Harbor Laboratory

09/13/2023

DOI: 10.1101/2023.07.20.549745

PMCID: PMC10515760

PMID: 37745359

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https://doi.org/10.1101/2023.07.20.549745View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2 -deletion leading to reduced metastasis and MLH1 -deletion to enhanced liver or lung metastasis. Mechanistically, MSH2 -deletion induces the expression of a panel of chemokines in BLBC via epigenetic and/or transcriptional regulation, which leads to an immune reactive tumor microenvironment (TME) and elevated immune cell infiltrations. MLH1 is not correlated with chemokine expression and/or immune cell infiltration in BLBC, but its deletion results in strong accumulation of neutrophils that are known for metastasis promotion. Our study supports the differential functions of MSH2 and MLH1 in BLBC progression and metastasis, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism.

Details

Title: Subtitle: Contrasting roles of different mismatch repair proteins in basal-like breast cancer
Creators: Jiao Mo - University of Florida
Nicholas Borcherding - University of Iowa
Sung Jo - University of Iowa
Tanzia Islam Tithi - University of Florida
Kailey E Cash
Masayoshi Honda - University of Iowa
Lei Wang
Kawther K. Ahmed - University of Iowa
Ronald Weigel - University of Iowa
Maria Spies - University of Iowa
Ryan Kolb - University of Florida
Weizhou Zhang - University of Florida Health
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.07.20.549745
PMID: 37745359
PMCID: PMC10515760
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 09/13/2023
Academic Unit: Dermatology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984472531002771

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