KRT13 promotes stemness and drives metastasis in breast cancer through a plakoglobin/c-Myc signaling pathway

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Abstract

Background

Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Keratin 13 (KRT13) plays an important role in breast cancer progression and metastasis. The objective of this study is to elucidate the mechanism by which KRT13 promotes breast cancer growth and metastasis.

Methods

The function and mechanisms of KRT13 in breast cancer progression and metastasis were assessed by overexpression and knockdown followed by examination of altered behaviors in breast cancer cells and in xenograft tumor formation in mouse mammary fat pad. Human breast cancer specimens were examined by immunohistochemistry and multiplexed quantum dot labeling analysis to correlate KRT13 expression to breast cancer progression and metastasis.

Results

KRT13-overexpressing MCF7 cells displayed increased proliferation, invasion, migration and in vivo tumor growth and metastasis to bone and lung. Conversely, KRT13 knockdown inhibited the aggressive behaviors of HCC1954 cells. At the molecular level, KRT13 directly interacted with plakoglobin (PG, γ-catenin) to form complexes with desmoplakin (DSP). This complex interfered with PG expression and nuclear translocation and abrogated PG-mediated suppression of c-Myc expression, while the KRT13/PG/c-Myc signaling pathway increased epithelial to mesenchymal transition and stem cell-like phenotype. KRT13 expression in 58 human breast cancer tissues was up-regulated especially at the invasive front and in metastatic specimens (12/18) ( p < 0.05). KRT13 up-regulation in primary breast cancer was associated with decreased overall patient survival.

Conclusions

This study reveals that KRT13 promotes breast cancer cell growth and metastasis via a plakoglobin/c-Myc pathway. Our findings reveal a potential novel pathway for therapeutic targeting of breast cancer progression and metastasis.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13058-022-01502-6.

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Most cited references 51

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Molecular portraits of human breast tumours.

Charles Perou, Therese Sørlie, Michael B. Eisen … (2001)

Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

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Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype.

Sara Ricardo, André Filipe Vieira, René Gerhard … (2011)

The study of CD44/CD24 and ALDH1 expression is the most accurate method to identify cancer stem cells (CSC) from breast cancer populations. However, the overlap between CD44(+)CD24(-/low) and ALDH1(high) CSC phenotypes in breast cancer seems to be very small, as well as their distribution among intrinsic breast cancer subtypes. Due to this discrepancy, it is imperative to improve the understanding of breast CSC marker distribution. 466 invasive breast carcinomas and eight breast cancer cell lines were analysed for the expression of CD44, CD24 and ALDH1, to evaluate their distribution among the distinct molecular subtypes. Basal-like tumours (76.5%) contained the higher percentage of cells with the CSC phenotype CD44(+)CD24(-/low) (p<0.0001). From ALDH1-positive cases, 39.4% were also basal-like tumours (p<0.0001). The analysis of breast cancer cell lines indicated that luminal cell lines are mainly enriched in a CD44(-/low)CD24(+) cell population, basal/mesenchymal breast cancer cell lines are enriched in the CD44(+)CD24(-/low) phenotype, whereas the remaining basal/epithelial cell lines are mainly positive for both markers. ALDH1 activity was mainly found in HER-OE and basal/epithelial breast cancer cell. CD44(+)CD24(-/low) and ALDH1(+) phenotypes seem to identify CSC with distinct levels of differentiation. It seems that the paramount method and biomarkers that identify breast CSC within the distinct molecular subtypes need to be better explored, because it is pivotal to translate the CSC concept to clinical practice. In the future, the recognition of reliable markers to distinguish the CSC pool in each molecular subtype will be decisive for the development of specific target therapies.

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Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay.

Sabine Riethdorf, Vanessa Vogel, Martin Ronald Sprick … (2013)

It has been hypothesized that carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, although the presence of CTCs is an indicator of poor prognosis in several carcinoma entities, the existence and phenotype of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. Here we developed a xenograft assay and used it to show that primary human luminal breast cancer CTCs contain MICs that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. In a small cohort of patients with metastases, the number of EPCAM(+)CD44(+)CD47(+)MET(+) CTCs, but not of bulk EPCAM(+) CTCs, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer.

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Author and article information

Contributors

Ruoxiang Wang:

ORCID: http://orcid.org/0000-0003-2614-8292

ruoxiang.wang@cshs.org

Journal

Journal ID (nlm-ta): Breast Cancer Res

Journal ID (iso-abbrev): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Electronic): 25 January 2022

Publication date PMC-release: 25 January 2022

Publication date (Print): 2022

Volume: 24

Electronic Location Identifier: 7

Affiliations

[1 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Department of Pathology, West China Hospital, , Sichuan University, ; Chengdu, Sichuan China

[2 ]GRID grid.50956.3f, ISNI 0000 0001 2152 9905, Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, , Cedars-Sinai Medical Center, ; 8750 Beverly Boulevard, Atrium 105, Los Angeles, CA 90048 USA

[3 ]GRID grid.50956.3f, ISNI 0000 0001 2152 9905, Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, , Cedars-Sinai Medical Center, ; Los Angeles, CA USA

[4 ]GRID grid.417119.b, ISNI 0000 0001 0384 5381, Department of Pathology, , VA Greater Los Angeles Healthcare System, ; Los Angeles, CA USA

[5 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Department of Urology, , University of Southern California Keck School of Medicine, ; Los Angeles, CA USA

Author information

Ruoxiang Wang http://orcid.org/0000-0003-2614-8292

Article

Publisher ID: 1502

DOI: 10.1186/s13058-022-01502-6

PMC ID: 8788068

PubMed ID: 35078507

SO-VID: 2ec55b62-f8bc-4eec-9775-13dedb29c19f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 30 April 2021

Date accepted : 13 January 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: CA098912

Award Recipient : Leland W. K. Chung

Funded by: FundRef http://dx.doi.org/10.13039/100013015, Cedars-Sinai Medical Center;

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer,metastasis,krt13,plakoglobin,γ-catenin,c-myc

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer, metastasis, krt13, plakoglobin, γ-catenin, c-myc

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KRT13 promotes stemness and drives metastasis in breast cancer through a plakoglobin/c-Myc signaling pathway

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Karger: Oncology

Most cited references 51

Molecular portraits of human breast tumours.

Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype.

Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay.

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Cited by 16

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