Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Nov 17;14(22):5643.
doi: 10.3390/cancers14225643.

Mechanistic and Clinical Evidence Supports a Key Role for Cell Division Cycle Associated 5 (CDCA5) as an Independent Predictor of Outcome in Invasive Breast Cancer

Yousif A Kariri  1   2   3 , Chitra Joseph  4 , Mansour A Alsaleem  1   3   5 , Khloud A Elsharawy  1   3   6 , Sami Alsaeed  1   3   7 , Michael S Toss  3   4 , Nigel P Mongan  8   9 , Andrew R Green  1   3 , Emad A Rakha  1   3   4
Affiliations

Mechanistic and Clinical Evidence Supports a Key Role for Cell Division Cycle Associated 5 (CDCA5) as an Independent Predictor of Outcome in Invasive Breast Cancer

Yousif A Kariri et al. Cancers (Basel). .

Abstract

Background: Cell Division Cycle Associated 5 (CDCA5) plays a role in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signalling pathway involving cell division, cancer cell migration and apoptosis. This study aims to assess the prognostic and biological value of CDCA5 in breast cancer (BC).

Methods: The biological and prognostic value of CDCA5 were evaluated at mRNA (n = 5109) and protein levels (n = 614) utilizing multiple well-characterized early stage BC cohorts. The effects of CDCA5 knockdown (KD) on multiple oncogenic assays were assessed in vitro using a panel of BC cell lines.

Results: this study examined cohorts showed that high CDCA5 expression was correlated with features characteristic of aggressive behavior and poor prognosis, including the presence of high grade, large tumor size, lymphovascular invasion (LVI), hormone receptor negativity and HER2 positivity. High CDCA5 expression, at both mRNA and protein levels, was associated with shorter BC-specific survival independent of other variables (p = 0.034, Hazard ratio (HR) = 1.6, 95% CI; 1.1-2.3). In line with the clinical data, in vitro models indicated that CDCA5 depletion results in a marked decrease in BC cell invasion and migration abilities and a significant accumulation of the BC cells in the G2/M-phase.

Conclusions: These results provide evidence that CDCA5 plays an important role in BC development and metastasis and could be used as a potential biomarker to predict disease progression in BC.

Keywords: CDCA5; breast cancer; prognosis; progression.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Distribution of mRNA and immunohistochemical expression of CDCA5 in BC. (A) RNA seq dataset comprising 1097 breast tumoral samples, 113 adjunct normal tissue and 7 metastatic samples were analyzed to evaluate CDCA5 expression using TNM data portal. (B) Evaluation of CDCA5 expression using PAM50 classification for BC obtained from UALCAN data portal. Representative immunohistochemical CDCA5 protein expression in invasive BC cores (power 20×). (C) CDCA5 strong cytoplasmic staining of invasive BC cells and (D) CDCA5 weak cytoplasmic staining of invasive BC cells.
Figure 2
Figure 2
Patient outcomes of BC survival on the METABRIC and the Nottingham BC cohorts. (A) Cumulative survival of BC patients stratified by CDCA5 mRNA expression in the KM-Plotter cohort. (B) Cumulative survival of BC patients stratified by CDCA5 mRNA expression in breast tumors in METABRIC. (C) Cumulative survival of BC patients stratified by CDCA5 mRNA expression in LVI-positive BC in METABRIC. (D) Cumulative survival of BC stratified by CDCA5 protein expression. (E) Cumulative survival of BC patients stratified by CDCA5 protein expression in the Nottingham LVI-positive cohort.
Figure 3
Figure 3
The protein expression of CDCA5 was evaluated in HER2-enriched (SKBR3) and TNBC (MDA MB-231) cell lines. (A) Western blot of CDCA5 levels in SKBR3 and MDA MB-231 BC cell lines transfected with CDCA5 siRNA and scrambled siRNA control. (B) Clonogenic survival assay for SKBR3, MDA MB-231 control and knockdown cells (C) Proliferation ability for SKBR3 and MDA MB-231 control and knockdown was evaluated using MTS assay. (D) Invasion assay quantification of SKBR3 & MDA MB-231 control and knockdown cells. p values are indicated as follows; ‘*’ p < 0.05, ‘**’ p < 0.01, ‘***’ p < 0.001. Error bar indicates standard error of the mean (SEM).
Figure 4
Figure 4
CDCA5 cancer cell migration and cell cycle result. (A–C), Representative images of wound closure assay in SKBR3 & MDA-MB 231 BC cell lines transfected with scrambled siRNA control and CDCA5 siRNA, wound measuring was performed in ImageJ software. (D–F). Representative images and quantification of cell cycle progression by flow cytometry in the SKBR3 and MDA MB-231 BC cell lines transfected with CDCA5 siRNA compared to control scrambled cells. p values are indicated as follows; ‘*’ p < 0.05, ‘**’ p < 0.01, ‘***’ p < 0.001. Error bar indicates standard error of the mean (SEM).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Aleskandarany M.A., Sonbul S.N., Mukherjee A., Rakha E.A. Molecular Mechanisms Underlying Lymphovascular Invasion in Invasive Breast Cancer. Pathobiology. 2015;82:113–123. doi: 10.1159/000433583. - DOI - PubMed
    1. Rakha E.A., Martin S., Lee A.H.S., Morgan D., Pharoah P.D.P., Hodi Z., Macmillan D., Ellis I.O. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer. 2012;118:3670–3680. doi: 10.1002/cncr.26711. - DOI - PubMed
    1. Kariri Y.A., Aleskandarany M.A., Joseph C., Kurozumi S., Mohammed O.J., Toss M.S., Green A.R., Rakha E.A. Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype. Pathobiology. 2020;87:218–231. doi: 10.1159/000508337. - DOI - PubMed
    1. Vijai J., Kirchhoff T., Schrader K.A., Brown J., Dutra-Clarke A.V., Manschreck C., Hansen N., Rau-Murthy R., Sarrel K., Przybylo J., et al. Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies. PLoS Genet. 2013;9:e1003220. doi: 10.1371/journal.pgen.1003220. - DOI - PMC - PubMed
    1. Johanneson B., Deutsch K., McIntosh L., Friedrichsen-Karyadi D.M., Janer M., Kwon E.M., Iwasaki L., Hood L., Ostrander E.A., Stanford J.L. Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer. Prostate. 2007;67:732–742. doi: 10.1002/pros.20528. - DOI - PubMed

Grants and funding

This research was supported and funded by the Saudi Arabia Ministry of Education Shaqra University. The authors are part of the PathLAKE digital pathology consortium. These new Centres are supported by a £50m investment from the Data to Early Diagnosis and Precision Medicine strand of the government’s Industrial Strategy Challenge Fund, managed and delivered by UK Research and Innovation (UKRI).