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Rampant centrosome amplification underlies more aggressive disease course of triple negative breast cancers.

Pannu V, Mittal K, Cantuaria G, Reid MD, Li X, Donthamsetty S, McBride M, Klimov S, Osan R, Gupta MV, Rida PC, Aneja R - Oncotarget (2015)

Bottom Line: Our data establish differences in incidence and severity of CA between TNBC and non-TNBC cell lines and clinical specimens.We found strong correlation between CA and aggressiveness markers associated with metastasis in 20 pairs of grade-matched TNBC and non-TNBC specimens (p < 0.02).Time-lapse imaging of MDA-MB-231 cells harboring amplified centrosomes demonstrated enhanced migratory ability.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

ABSTRACT
Centrosome amplification (CA), a cell-biological trait, characterizes pre-neoplastic and pre-invasive lesions and is associated with tumor aggressiveness. Recent studies suggest that CA leads to malignant transformation and promotes invasion in mammary epithelial cells. Triple negative breast cancer (TNBC), a histologically-aggressive subtype shows high recurrence, metastases, and mortality rates. Since TNBC and non-TNBC follow variable kinetics of metastatic progression, they constitute a novel test bed to explore if severity and nature of CA can distinguish them apart. We quantitatively assessed structural and numerical centrosomal aberrations for each patient sample in a large-cohort of grade-matched TNBC (n = 30) and non-TNBC (n = 98) cases employing multi-color confocal imaging. Our data establish differences in incidence and severity of CA between TNBC and non-TNBC cell lines and clinical specimens. We found strong correlation between CA and aggressiveness markers associated with metastasis in 20 pairs of grade-matched TNBC and non-TNBC specimens (p < 0.02). Time-lapse imaging of MDA-MB-231 cells harboring amplified centrosomes demonstrated enhanced migratory ability. Our study bridges a vital knowledge gap by pinpointing that CA underlies breast cancer aggressiveness. This previously unrecognized organellar inequality at the centrosome level may allow early-risk prediction and explain higher tumor aggressiveness and mortality rates in TNBC patients.

No MeSH data available.


Related in: MedlinePlus

Breast tumors with higher CAI have lower survival rate compared to low CAI tumors(A) Overall survival plots for high and low CAI groups. High CAI patients had lower overall survival (n = 84) compared to low CAI patients (n = 78) in in silico data. (B) Scatter-plot comparing the CAI in TNBC and grade-matched non-TNBC patients (p < 0.001 for Grade II TNBC and non-TNBC patients). (C) Bar graphs comparing the CAI in TNBC and non-TNBC patients considering stages (p < 0.005 for stage-matched TNBC and non-TNBC patients). (Lower n number in the survival analysis is due to the limited availability of survival data for all patients in the referred databases.)
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Figure 1: Breast tumors with higher CAI have lower survival rate compared to low CAI tumors(A) Overall survival plots for high and low CAI groups. High CAI patients had lower overall survival (n = 84) compared to low CAI patients (n = 78) in in silico data. (B) Scatter-plot comparing the CAI in TNBC and grade-matched non-TNBC patients (p < 0.001 for Grade II TNBC and non-TNBC patients). (C) Bar graphs comparing the CAI in TNBC and non-TNBC patients considering stages (p < 0.005 for stage-matched TNBC and non-TNBC patients). (Lower n number in the survival analysis is due to the limited availability of survival data for all patients in the referred databases.)

Mentions: Previous studies in solid tumors have alluded to an association between centrosomal abnormalities and advanced disease, aneuploidy, and an aggressive clinical course. These studies however lacked rigorous quantitation of the centrosomal abnormalities and have not explored whether centrosomal abnormalities are accompanied by any changes in the expression patterns of centrosomal genes. Given that there are differences in aggressive behavior between TNBC and non-TNBC patients, we investigated whether these histologically-distinct breast cancer subtypes might differ in the expression levels of centrosomal genes. To this end, we mined publically-available microarray data of breast cancer patients to evaluate gene expression levels for major structural centrosomal proteins, both centriolar (centrin) and pericentriolar (pericentrin and γ-tubulin). To gain deeper insights into centrosomal aberrations, we included genes whose dysregulation is implicated in CA (polo-like kinase 4 and cyclin E). We calculated a cumulative gene expression-based centrosome amplification index (CAI) by adding log transformed, normalized gene expression for CETN2 (centrin-2), TUBG1 (γ-tubulin), PCNT2 (pericentrin), PLK4 (polo-like kinase 4) and CCNE1 (cyclin E) genes. Given that cancer is a clonally evolving disease and CA could arise due to dysregulation of different genes in different cancers and even distinct cancer cell clones, we chose to select a panel of five centrosomal genes instead of a single gene. First, we evaluated the relationship of higher CA, as assessed by CAI, with disease aggressiveness, as determined by overall survival (OS). OS was calculated as the number of days from diagnosis to death or last follow-up if death was not recorded. Irrespective of receptor status (TNBC n = 101, non-TNBC n = 61), patients with higher CAI (n = 78) had lower OS (p = 0.049) than patients with lower CAI (n = 84) (Fig. 1A). Intriguingly, high CAI group was composed of ~60% TNBC cases whereas the low CAI group composed of ~38% TNBC cases, thus indicating that TNBCs tend to have higher CAI as compared to non-TNBCs. Further analysis of another dataset of 138 TNBC and 466 non-TNBC samples clearly showed significantly higher CAI in TNBCs compared to non-TNBCs, even when they were (a) grade-matched (Fig. 1B), or (b) stage-matched (Fig. 1C).


Rampant centrosome amplification underlies more aggressive disease course of triple negative breast cancers.

Pannu V, Mittal K, Cantuaria G, Reid MD, Li X, Donthamsetty S, McBride M, Klimov S, Osan R, Gupta MV, Rida PC, Aneja R - Oncotarget (2015)

Breast tumors with higher CAI have lower survival rate compared to low CAI tumors(A) Overall survival plots for high and low CAI groups. High CAI patients had lower overall survival (n = 84) compared to low CAI patients (n = 78) in in silico data. (B) Scatter-plot comparing the CAI in TNBC and grade-matched non-TNBC patients (p < 0.001 for Grade II TNBC and non-TNBC patients). (C) Bar graphs comparing the CAI in TNBC and non-TNBC patients considering stages (p < 0.005 for stage-matched TNBC and non-TNBC patients). (Lower n number in the survival analysis is due to the limited availability of survival data for all patients in the referred databases.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496369&req=5

Figure 1: Breast tumors with higher CAI have lower survival rate compared to low CAI tumors(A) Overall survival plots for high and low CAI groups. High CAI patients had lower overall survival (n = 84) compared to low CAI patients (n = 78) in in silico data. (B) Scatter-plot comparing the CAI in TNBC and grade-matched non-TNBC patients (p < 0.001 for Grade II TNBC and non-TNBC patients). (C) Bar graphs comparing the CAI in TNBC and non-TNBC patients considering stages (p < 0.005 for stage-matched TNBC and non-TNBC patients). (Lower n number in the survival analysis is due to the limited availability of survival data for all patients in the referred databases.)
Mentions: Previous studies in solid tumors have alluded to an association between centrosomal abnormalities and advanced disease, aneuploidy, and an aggressive clinical course. These studies however lacked rigorous quantitation of the centrosomal abnormalities and have not explored whether centrosomal abnormalities are accompanied by any changes in the expression patterns of centrosomal genes. Given that there are differences in aggressive behavior between TNBC and non-TNBC patients, we investigated whether these histologically-distinct breast cancer subtypes might differ in the expression levels of centrosomal genes. To this end, we mined publically-available microarray data of breast cancer patients to evaluate gene expression levels for major structural centrosomal proteins, both centriolar (centrin) and pericentriolar (pericentrin and γ-tubulin). To gain deeper insights into centrosomal aberrations, we included genes whose dysregulation is implicated in CA (polo-like kinase 4 and cyclin E). We calculated a cumulative gene expression-based centrosome amplification index (CAI) by adding log transformed, normalized gene expression for CETN2 (centrin-2), TUBG1 (γ-tubulin), PCNT2 (pericentrin), PLK4 (polo-like kinase 4) and CCNE1 (cyclin E) genes. Given that cancer is a clonally evolving disease and CA could arise due to dysregulation of different genes in different cancers and even distinct cancer cell clones, we chose to select a panel of five centrosomal genes instead of a single gene. First, we evaluated the relationship of higher CA, as assessed by CAI, with disease aggressiveness, as determined by overall survival (OS). OS was calculated as the number of days from diagnosis to death or last follow-up if death was not recorded. Irrespective of receptor status (TNBC n = 101, non-TNBC n = 61), patients with higher CAI (n = 78) had lower OS (p = 0.049) than patients with lower CAI (n = 84) (Fig. 1A). Intriguingly, high CAI group was composed of ~60% TNBC cases whereas the low CAI group composed of ~38% TNBC cases, thus indicating that TNBCs tend to have higher CAI as compared to non-TNBCs. Further analysis of another dataset of 138 TNBC and 466 non-TNBC samples clearly showed significantly higher CAI in TNBCs compared to non-TNBCs, even when they were (a) grade-matched (Fig. 1B), or (b) stage-matched (Fig. 1C).

Bottom Line: Our data establish differences in incidence and severity of CA between TNBC and non-TNBC cell lines and clinical specimens.We found strong correlation between CA and aggressiveness markers associated with metastasis in 20 pairs of grade-matched TNBC and non-TNBC specimens (p < 0.02).Time-lapse imaging of MDA-MB-231 cells harboring amplified centrosomes demonstrated enhanced migratory ability.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

ABSTRACT
Centrosome amplification (CA), a cell-biological trait, characterizes pre-neoplastic and pre-invasive lesions and is associated with tumor aggressiveness. Recent studies suggest that CA leads to malignant transformation and promotes invasion in mammary epithelial cells. Triple negative breast cancer (TNBC), a histologically-aggressive subtype shows high recurrence, metastases, and mortality rates. Since TNBC and non-TNBC follow variable kinetics of metastatic progression, they constitute a novel test bed to explore if severity and nature of CA can distinguish them apart. We quantitatively assessed structural and numerical centrosomal aberrations for each patient sample in a large-cohort of grade-matched TNBC (n = 30) and non-TNBC (n = 98) cases employing multi-color confocal imaging. Our data establish differences in incidence and severity of CA between TNBC and non-TNBC cell lines and clinical specimens. We found strong correlation between CA and aggressiveness markers associated with metastasis in 20 pairs of grade-matched TNBC and non-TNBC specimens (p < 0.02). Time-lapse imaging of MDA-MB-231 cells harboring amplified centrosomes demonstrated enhanced migratory ability. Our study bridges a vital knowledge gap by pinpointing that CA underlies breast cancer aggressiveness. This previously unrecognized organellar inequality at the centrosome level may allow early-risk prediction and explain higher tumor aggressiveness and mortality rates in TNBC patients.

No MeSH data available.


Related in: MedlinePlus