Diaphanous-related formin-3 overexpression inhibits the migration and invasion of triple-negative breast cancer by inhibiting RhoA-GTP expression.

Triple-negative breast cancer (TNBC) is associated with a high risk of metastasis, recurrence, and poor prognosis. TNBC is insensitive to existing endocrine and targeted breast cancer therapies because it lacks the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Therefore, there is an urgent need for identifying novel targets to improve the efficacy of TNBC treatment. Diaphanous-related formin-3 (DIAPH3) regulates cytoskeleton formation to regulate cell adhesion, migration, and differentiation. A previous study showed that DIAPH3 promoted the metastasis of prostate cancer. However, DIAPH3 expression in TNBC and its effect on TNBC development have not been reported to date. In present study, we investigated the expression and functions of DIAPH3 in TNBC. Results of immunohistochemical staining showed that DIAPH3 expression significantly decreased in breast cancer tissues, especially TNBC tissues, compared with that in paired non-tumor tissues. In addition, DIAPH3 expression was associated with TNM stage and lymph node metastasis, but not with tumor size in patients with TNBC. Further, DIAPH3 overexpression clearly suppressed the migration and invasion of MDA-MB-231 cells and decreased the expression of Ras Homolog Family Member A (RhoA), RhoA-GTP, Matrix Metallopeptidase 2 (MMP-2), and MMP-9. Thus, we predict that DIAPH3 overexpression inhibits the migration and invasion of TNBC by inhibiting RhoA-GTP expression and the results of the present study provide new insights for developing DIAPH3-targeting therapies for TNBC.

Jiang J 《-》

miR-613 inhibits cell migration and invasion by downregulating Daam1 in triple-negative breast cancer.

Dishevelled-associated activator of morphogenesis 1 (Daam1) is a formin protein and participates in regulating cell migration of triple-negative breast cancer (TNBC) cells. The specific miRNA targeting Daam1 and mediating cell migration and invasion remains obscure. This experiment investigated the suppressive role of miR-613 in TNBC cells. The luciferase activity of Daam1 3'-untranslated region (3'-UTR) based reporters constructed in HEK-293T and MCF-7 cells suggested that Daam1 was the target gene of miR-613. Overexpressed miR-613 reduced the protein level of Daam1, weakened RhoA activity, and retarded the cell migration, cell invasion and colony formation of TNBC cells. Overexpression of Daam1 or RhoA rescued cell migration and invasion in miR-613-overexpressed TNBC cells, but failed to reverse colony formation. MiR-613 was significantly downregulated in breast cancer tissues compared with that in adjacent normal tissues. This downregulation in TNBC tissues and lymphnode metastatic breast cancer tissues was more obvious than that in non-TNBC tissues and non-metastatic cancer tissues, respectively. MiR-613 weakens the resistance of TNBC cells against paclitaxel rather than adriamycin, cyclophosphamide, docetaxel, and kaempferol. Taken together, miR-613 is involved in cell migration and invasion of TNBC cells via targeting Daam1/RhoA signaling pathway.

Xiong H ，Yan T ，Zhang W ，Shi F ，Jiang X ，Wang X ，Li S ，Chen Y ，Chen C ，Zhu Y ... -  《-》

Rhophilin-associated tail protein 1 promotes migration and metastasis in triple negative breast cancer via activation of RhoA.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with high motile and invasive capacity that contributes to metastasis. Understanding the mechanisms for the motility of TNBC might provide novel targetable vulnerabilities of the tumors. Herein, we find that Rhophilin-associated tail protein 1 (ROPN1) is selectively overexpressed in human TNBC cell lines and tissues. Overexpression of ROPN1 promotes, while silencing of ROPN1 inhibits the robust migration, invasion, and in vivo metastasis of TNBC cells. Moreover, we find that ROPN1 activates RhoA signaling via rhophilin-1 (RHPN1), leading to enhanced actin stress fibers formation in TNBC cells. RhoA signaling is demonstrated to be essential for ROPN1-mediated migration and metastasis of TNBC cells. Finally, we find that high levels of ROPN1 are significantly associated distant metastasis and predicted poor prognosis in patients with breast cancer. These findings reveal a novel mechanism for the high motility and metastasis of TNBC cells, suggesting that ROPN1 might be a potential prognostic marker and therapeutic target.

Liu Q ，Huang X ，Li Q ，He L ，Li S ，Chen X ，Ouyang Y ，Wang X ，Lin C ... -  《-》

Zerumbone suppresses the motility and tumorigenecity of triple negative breast cancer cells via the inhibition of TGF-β1 signaling pathway.

Kim S ，Lee J ，Jeon M ，Lee JE ，Nam SJ ... -  《Oncotarget》

PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.

Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells.

Gari HH ，DeGala GD ，Ray R ，Lucia MS ，Lambert JR ... -  《-》