Journal article
Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer
Cancer research communications, Vol.3(1), pp.54-65
01/01/2023
DOI: 10.1158/2767-9764.CRC-22-0302
PMCID: PMC10035514
PMID: 36968230
Abstract
Chromosomal instability (CIN), the persistent reshuffling of chromosomes during mitosis, is a hallmark of human cancers that contributes to tumor heterogeneity and has been implicated in driving metastasis and altering responses to therapy. Though multiple mechanisms can produce CIN, lagging chromosomes generated from abnormal merotelic attachments are the major cause of CIN in a variety of cell lines, and are expected to predominate in cancer. Here, we quantify CIN in breast cancer using a tumor microarray, matched primary and metastatic samples, and patient-derived organoids from primary breast cancer. Surprisingly, misaligned chromosomes are more common than lagging chromosomes and represent a major source of CIN in primary and metastatic tumors. This feature of breast cancers is conserved in a majority of breast cancer cell lines. Importantly, though a portion of misaligned chromosomes align before anaphase onset, the fraction that remain represents the largest source of CIN in these cells. Metastatic breast cancers exhibit higher rates of CIN than matched primary cancers, primarily due to increases in misaligned chromosomes. Whether CIN causes immune activation or evasion is controversial. We find that misaligned chromosomes result in immune-activating micronuclei substantially less frequently than lagging and bridge chromosomes and that breast cancers with greater frequencies of lagging chromosomes and chromosome bridges recruit more stromal tumor-infiltrating lymphocytes. These data indicate misaligned chromosomes represent a major mechanism of CIN in breast cancer and provide support for differential immunostimulatory effects of specific types of CIN.
We surveyed the single-cell landscape of mitotic defects that generate CIN in primary and metastatic breast cancer and relevant models. Misaligned chromosomes predominate, and are less immunostimulatory than other chromosome segregation errors.
Details
- Title: Subtitle
- Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer
- Creators
- John B Tucker - University of Wisconsin–MadisonSarah C Bonema - University of Wisconsin–MadisonRebeca García-Varela - University of Wisconsin–MadisonRyan A Denu - University of Wisconsin–MadisonYang Hu - University of Wisconsin–MadisonStephanie M McGregor - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin–MadisonBeth A Weaver - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Cancer research communications, Vol.3(1), pp.54-65
- DOI
- 10.1158/2767-9764.CRC-22-0302
- PMID
- 36968230
- PMCID
- PMC10035514
- NLM abbreviation
- Cancer Res Commun
- ISSN
- 2767-9764
- eISSN
- 2767-9764
- Grant note
- T32 CA009135 / NCI NIH HHS T32 GM141013 / NIGMS NIH HHS T32 GM008688 / NIGMS NIH HHS P30 CA014520 / NCI NIH HHS T32 GM140935 / NIGMS NIH HHS R01 CA234904 / NCI NIH HHS
- Language
- English
- Date published
- 01/01/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701253202771
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