Abstract
TGF-β plays an important role in breast cancer progression as a prometastatic factor, notably through enhancement of cell migration. It is becoming clear that microRNAs, a new class of small regulatory molecules, also play crucial roles in mediating tumor formation and progression. We found TGF-β to down-regulate the expression of the microRNA miR-584 in breast cancer cells. Furthermore, we identified PHACTR1, an actin-binding protein, to be positively regulated by TGF-β in a miR-584-dependent manner. Moreover, we found TGF-β-mediated down-regulation of miR-584 and increased expression of PHACTR1 to be required for TGF-β-induced cell migration of breast cancer cells. Indeed, both overexpression of miR-584 and knockdown of PHACTR1 resulted in a drastic reorganization of the actin cytoskeleton and reduced TGF-β-induced cell migration. Our data highlight a novel signaling route whereby TGF-β silences the expression of miR-584, resulting in enhanced PHACTR1 expression, and further leading to actin rearrangement and breast cancer cell migration.
Highlights
TGF- promotes cell migration in advanced breast cancer
We used a panel of basal breast cancer cell lines, including MDA-MB-231, a highly invasive cell line extracted from the pleural effusion of an adenocarcinoma that relapsed several years after the removal of the primary tumor [41, 43], SCP2 cells that were derived from MDA-MB-231 cells and that express a bone metastatic gene signature, SUM159PT, a highly invasive cell line derived from the anaplastic carcinoma of a primary breast cancer [41], and SUM149PT, a cell line with both basal-like and luminal-like features extracted from the inflammatory ductal carcinoma of a primary breast tumor [41, 44]
To investigate whether the antimigratory effects of miR-584 downstream of TGF- are restricted to cells derived from the breast tissue, we examined the microRNA on TGF--mediated cell migration in other cell types, including HaCaT, an immortalized human keratinocyte cell line, HuH7, an epithelium-like tumorigenic cell line derived from a liver tumor, and PC3, a cell line derived from bone metastasis of a stage IV prostate cancer patient
Summary
TGF- promotes cell migration in advanced breast cancer. Results: TGF- down-regulates miR-584, leading to a PHACTR1 overexpression, and both are involved in cell migration and actin reorganization. We found TGF--mediated down-regulation of miR-584 and increased expression of PHACTR1 to be required for TGF--induced cell migration of breast cancer cells. It is thought that these partner proteins, which act as co-activators or co-repressors, are differentially expressed in different cell types, providing a basis for tissue- and cell type-specific functions of TGF- [17] One such co-factor is the p68 helicase of the microprocessor complex, which participates in the processing of microRNA (miRNA) maturation. Considering the role of TGF- in breast cancer cell migration and the emerging role played by these miRNAs in human cancer, we investigated whether they acted downstream of TGF--mediated tumor progression. We identified miR-584, a potential tumor suppressor [32], as a novel target of TGF- and found that miR-584 expression was negatively regulated by this growth factor in a number of breast cancer cells. Our results highlight miR-584 and its downstream target, PHACTR1, as a central regulatory axis, which participates in TGF--induced cell migration in invasive breast cancer cells
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