Downregulation of miR‐106b induced breast cancer cell invasion and motility in association with overexpression of matrix metalloproteinase 2

Abstract

Breast cancer (BC) is one of the most common cancers in women, and it can often metastasize to the bone. The mechanism of BC bone metastasis remains unclear and requires in-depth investigation. In a previous study, we found the expression of matrix metalloproteinase 2 (MMP2) to be significantly more pronounced at metastatic bone sites than at orthotopic sites. MicroRNA expression profiling showed miR-106b to be markedly downregulated during BC bone metastasis. However, the specific manner in which MMP2 and miR-106b are involved in the BC bone metastasis is still unclear. In the present study, we found MMP2 expression in orthotopic tumor tissue to be related to the risk of bone metastasis in BC patients. MiR-106b levels in orthotopic tumor tissue showed a negative correlation with MMP2 expression and breast cancer bone metastasis. MMP2 was shown to be a direct target of miR-106b. Both gain- and loss-of-function studies showed that MMP2 could promote the migration and invasion of BC cells and that miR-106b could suppress both. The blockage of MMP2 by RNA interference mimicked the anti-migration and anti-invasion effects of miR-106b, and introduction of MMP2 antagonized the function of miR-106b. MMP2 was also found to regulate the ERK signaling cascade and so adjust the bone microenvironment to favor osteoclastogenesis and bone metastasis. These results suggest that MMP2 upregulation plays an important role in BC bone metastasis through ERK pathways, and miR-106b directly regulates MMP2 expression. The miR-106b/MMP2/ERK pathway may be a promising therapeutic target for inhibiting BC bone metastasis.

Evaluation of Cell-Free Urine microRNAs Expression for the Use in Diagnosis of Ovarian and Endometrial Cancers. A Pilot Study

“…For endometrial cancer, there is generally lack of information on miR-106b expression, but miR-106b has been showing an association with invasive endometrial cells while being under-expressed [25]. Recently, down-regulation of miR-106b has been demonstrated to result in MMP2 over-expression, consequently leading to the increased invasion and metastasis in breast cancer [26].…”

Sulforaphane inhibited tumor necrosis factor-α induced migration and invasion in estrogen receptor negative human breast cancer cells

“…MMP-2 expression regulated by miR-106b was reported to enhance breast cancer metastasis to the bone via the ERK signaling pathway (16). Higher tissue expression of MMP-9 was positively correlated to lymph node metastasis and aggressiveness in breast cancer patients (17).…”

Usefulness of miRNA profiles for predicting pathological responses to neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer

“…Twenty-one miRNAs were differentially expressed between the non-pCR and pCR groups in the analysis of all 40 patients with HER2-positive breast cancer (Table III). Nine of these 21 miRNAs are reported to be associated with breast cancer (17)(18)(19)(20)(21)(22)(23)(24)(25). The other 12 miRNAs have no reported correlation with breast cancer.…”

“…For the luminal B-like (HER2-positive) subtype, 17 miRNAs were differentially expressed (Table IV), and nine of these 17 miRNAs are reported to be correlated with breast cancer (20)(21)(22)24,(26)(27)(28)(29)(30). For the HER2-positive (non luminal) subtype, 14 miRNAs were differentially expressed (Table V), and five of these are reported to be correlated with breast cancer (17,23,25,31,32). The miRNA expression profiles associated with pathological response differed completely between the HER2-positive (non luminal) and luminal B-like (HER2-positive) subtypes.…”