Limits...
AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128.

Eterno V, Zambelli A, Villani L, Tuscano A, Manera S, Spitaleri A, Pavesi L, Amato A - Sci Rep (2016)

Bottom Line: In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells.As a consequence, the amount of BCICs and their migratory capability dramatically decreased.In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

View Article: PubMed Central - PubMed

Affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.

ABSTRACT
AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and β-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

No MeSH data available.


Related in: MedlinePlus

Tumorigenic primary breast cancer cells showed higher levels of AurkA.(A) Primary breast cancer cells showing increased expression of AurkA (KBr2, KBr3, KBr4, bottom panel) exhibited a more aggressive phenotype evaluated as the capacity to generate tumors after injection into immune-compromised mice (top panel), expression of Mmp9, a metastatic marker, and Ki67 high levels (>10%). (B) CD44-positive cells from KBr2, KBr3 and KBr4 showed higher AurkA and wnt3a expression levels in comparison with CD44-negative cells (control), and increased migratory activity evaluated at 24 and 48 hours from seeding (respectively 24 h and 48 h). (C) AurkA knock-down (shAurkA) severely affected AurkA and wnt3a cDNAs levels, adhesion-indipendent growth and migratory activity in KBr2 cells as compared with control cells (empty). Moreover, it reduced levels of AurkA, β–catenin, Wnt3a, Stat3 and Mmp9 proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4920028&req=5

f4: Tumorigenic primary breast cancer cells showed higher levels of AurkA.(A) Primary breast cancer cells showing increased expression of AurkA (KBr2, KBr3, KBr4, bottom panel) exhibited a more aggressive phenotype evaluated as the capacity to generate tumors after injection into immune-compromised mice (top panel), expression of Mmp9, a metastatic marker, and Ki67 high levels (>10%). (B) CD44-positive cells from KBr2, KBr3 and KBr4 showed higher AurkA and wnt3a expression levels in comparison with CD44-negative cells (control), and increased migratory activity evaluated at 24 and 48 hours from seeding (respectively 24 h and 48 h). (C) AurkA knock-down (shAurkA) severely affected AurkA and wnt3a cDNAs levels, adhesion-indipendent growth and migratory activity in KBr2 cells as compared with control cells (empty). Moreover, it reduced levels of AurkA, β–catenin, Wnt3a, Stat3 and Mmp9 proteins.

Mentions: We analyzed correlation between AurkA expression and tumorigenic properties of cancer cells. We found that only 3 samples (KBr2, KBr3 and KBr4), showing a high expression of the kinase (similar to MDA-MB-231 cells), were tumorigenic. In contrast, AurkA-low expressing KBr1 failed to generate tumors after injection in vivo, as MCF7 cells (Fig. 4A).


AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128.

Eterno V, Zambelli A, Villani L, Tuscano A, Manera S, Spitaleri A, Pavesi L, Amato A - Sci Rep (2016)

Tumorigenic primary breast cancer cells showed higher levels of AurkA.(A) Primary breast cancer cells showing increased expression of AurkA (KBr2, KBr3, KBr4, bottom panel) exhibited a more aggressive phenotype evaluated as the capacity to generate tumors after injection into immune-compromised mice (top panel), expression of Mmp9, a metastatic marker, and Ki67 high levels (>10%). (B) CD44-positive cells from KBr2, KBr3 and KBr4 showed higher AurkA and wnt3a expression levels in comparison with CD44-negative cells (control), and increased migratory activity evaluated at 24 and 48 hours from seeding (respectively 24 h and 48 h). (C) AurkA knock-down (shAurkA) severely affected AurkA and wnt3a cDNAs levels, adhesion-indipendent growth and migratory activity in KBr2 cells as compared with control cells (empty). Moreover, it reduced levels of AurkA, β–catenin, Wnt3a, Stat3 and Mmp9 proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920028&req=5

f4: Tumorigenic primary breast cancer cells showed higher levels of AurkA.(A) Primary breast cancer cells showing increased expression of AurkA (KBr2, KBr3, KBr4, bottom panel) exhibited a more aggressive phenotype evaluated as the capacity to generate tumors after injection into immune-compromised mice (top panel), expression of Mmp9, a metastatic marker, and Ki67 high levels (>10%). (B) CD44-positive cells from KBr2, KBr3 and KBr4 showed higher AurkA and wnt3a expression levels in comparison with CD44-negative cells (control), and increased migratory activity evaluated at 24 and 48 hours from seeding (respectively 24 h and 48 h). (C) AurkA knock-down (shAurkA) severely affected AurkA and wnt3a cDNAs levels, adhesion-indipendent growth and migratory activity in KBr2 cells as compared with control cells (empty). Moreover, it reduced levels of AurkA, β–catenin, Wnt3a, Stat3 and Mmp9 proteins.
Mentions: We analyzed correlation between AurkA expression and tumorigenic properties of cancer cells. We found that only 3 samples (KBr2, KBr3 and KBr4), showing a high expression of the kinase (similar to MDA-MB-231 cells), were tumorigenic. In contrast, AurkA-low expressing KBr1 failed to generate tumors after injection in vivo, as MCF7 cells (Fig. 4A).

Bottom Line: In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells.As a consequence, the amount of BCICs and their migratory capability dramatically decreased.In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

View Article: PubMed Central - PubMed

Affiliation: Lab of Experimental Oncology &Pharmacogenomics IRCCS Fondazione "Salvatore Maugeri", Pavia, Italy.

ABSTRACT
AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and β-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

No MeSH data available.


Related in: MedlinePlus