We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression.
We found that the multi-tyrosine kinase inhibitor linifanib could significantly inhibit miR-10b and reverse its oncogenic function in breast cancer and liver cancer both in vitro and in vivo.
We found that differential miRNA expression in breast cancer could be variable between Lebanese and Western populations. miR-10b was positively correlated with the ER and PR status and miR-155 could be a noteworthy biomarker for the menopausal state, age at diagnosis, PR and Her2 status.
Unexpectedly, three miRs (miR-21, miR-10b and miR-31) demonstrated significantly higher level of expression in biBC vs. uBC (P = 0.0001, 0.00004 and 0.0002, respectively).
This was supported by analysis of breast cancer cells, which showed that loss of E-cadherin in metastatic cells is accompanied by elevation of miR-10b and interestingly, by a marked increase in accumulation of c-Jun.
These data provide a mechanism for the regulation of Tiam1-mediated Rac activation in breast cancer cells and need to be considered in the context of other reported functions for miR-10b.
The set of miRNAs hsa-mir-146a, hsa-mir-93, hsa-mir-375, hsa-mir-205, hsa-mir-15a, hsa-mir-21, hsa-mir-20a, hsa-mir-503, hsa-mir-29c, hsa-mir-497, hsa-mir-107, hsa-mir-125a, hsa-mir-200c, hsa-mir-212, hsa-mir-429, hsa-mir-34a, hsa-let-7c, hsa-mir-92b, hsa-mir-33a, hsa-mir-15b, hsa-mir-224, hsa-mir-185 and hsa-mir-10b integrate a profile that critically regulates the expression of the mRNA coding for Smad7 in breast cancer.
The relative concentrations of breast cancer-associated miR10b, miR34a, miR141 and miR155 were measured in the blood serum of 89 patients with primary breast cancer (M0, n = 59) and metastatic disease (M1, n = 30), and 29 healthy women by a TaqMan MicroRNA Assay.
The plasma expression of the miR-21, miR-155, and miR-10b was significantly increased and the Let-7a plasma expression decreased in the breast cancer patients compromised to the control ones.
The link between altered miRNA signatures and breast cancer development and metastasis can be observed either through the loss of tumor suppressor miRNAs, such as let-7s, miR-30a/31/34a/125s/200s/203/205/206/342 or the overexpression of oncogenic miRNAs, such as miR-10b/21/135a/155/221/222/224/373/520c in breast cancer cells.
The 20 most significant miRNAs differentially expressed in breast cancer tumors included miRNA (miR)-21, miR-10b, and miR-145, previously shown to be dysregulated in breast cancer.
Rho-GTPase-dependent modulation of cytoskeletal function and downregulation of E-cadherin expression are identified as relevant effectors of the miR-10b-syndecan-1 axis, which emerges as a promising target for the development of new therapeutic approaches for breast cancer.
Patients with non-metastatic HER2(+) breast cancer had higher serum miR-21 median levels than patients with non-metastatic HER2(-) disease (p = 0.044); whereas patients with metastatic HER2(+) breast cancer had higher serum miR-10b median levels than patients with metastatic HER2(-) disease (p = 0.0004).
Overall, these results establish that TWIST1 facilitates breast cancer bone metastasis formation through a mechanism dependent of miR-10b, which leads to increase tumor burden and bone destruction.
Our results provide evidences that the addition of miR-10b RERs to the prognostic factors used in clinical routine could improve the prediction abilities for both overall mortality and disease progression in breast cancer patients.
Only the has-miR-10b involved in breast cancer invasion and metastasis and has-miR-512-3p appeared to be up-regulated (2-3-fold) in all three cell lines.
On the basis of these findings, it is plausible that reactivation of CCN5 in miR-10b-positive invasive/metastatic breast cancers alone or in combination with current therapeutic regimens could provide a unique, alternative strategy to existing breast cancer therapy.
Moreover, five long noncoding RNAs that could competitively bind with miR-10b, respectively, named ACTA2-AS1, RP11-384P7.7, RP11-327J17.9, RP11-124N14.3, and RP11-645C24.5, were discovered as an integration signature with great potential in the prediction of survival outcomes in patients with different stages of breast cancer.