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WNT5A is abnormally increased in a variety of cancers including breast cancer and has an adverse effect on the prognosis. However, the biological function of WNT5A is not fully known in HER2-positive (HER2+) breast cancer. Using public clinical data, we analyzed disease-free survival (DFS) and distant metastasis-free survival (DMFS). Here, we found that abnormal WNT5A induction is a correlation with the poor prognosis of HER2+ breast cancer. WNT5A expression was also decreased by pan-HER inhibitor neratinib but not by trastuzumab. In addition, WNT5A augmented cell invasiveness of HER2+ breast-cancer cells. To find WNT5A-induced metastatic-related factors, we did a human cytokine array. The levels of GM-CSF and CXCL8 were significantly increased by WNT5A. CXCL8 also accelerated cell invasiveness in HCC1954 breast-cancer cells. The expression of CXCL8 induced by WNT5A has been significantly reduced by MEK inhibitor, binimetinib. Finally, we studied the effect of CXCR2 antagonist, SB225002, to verify the relevance of CXCL8 in WNT5A-induced cell invasion. As expected, we found that WNT5A-induced cell invasion is completely inhibited by SB225002. Taken together, we have demonstrated that WNT5A directly mediates cell invasion through the induction of CXCL8 and ultimately affects the survival rate of HER2+ breast cancer. [ABSTRACT FROM AUTHOR]

Basal-like breast cancer (BLBC) has a clinically aggressive nature. It is prevalent in young women and is known to often relapse rapidly. To date, the molecular mechanisms regarding the aggressiveness of BLBC have not been fully understood. In the present study, mechanisms of aggressiveness of BLBC involving EGFR and/or HER2 expression and interactions between tumor and tumor-associated macrophages (TAMs) were explored. The prognosis of breast cancer patients who underwent surgery at Samsung Medical Center was analyzed. It was found that the co-expression of EGFR and HER2 was associated with a worse prognosis. Therefore, we generated EGFR-positive BLBC cells with stable HER2 overexpression and analyzed the profile of secretory cytokines. Chemokine (C-C motif) ligand 2 (CCL2) expression was increased in HER2-overexpressed BLBC cells. Recombinant human CCL2 treatment augmented the motility of TAMs. In addition, the conditioned culture media of HER2-overexpressed BLBC cells increased the motility of TAMs. Furthermore, activation of TAMs by CCL2 or the conditioned culture media of HER2-overexpressed cells resulted in the production of pro-inflammatory cytokines, such as IL-8 and IL-1β. These observations reveal that CCL2 derived from EGFR and HER2 co-expressed BLBC cells can lead to increased TAM recruitment and the induction of IL-8 and IL-1β from recruited TAMs, triggering the tumorigenesis of breast cancer with the expression of both EGFR and HER2. Our findings demonstrate that EGFR+ and HER2+ BLBC aggressiveness is partially mediated through the interaction between BLBC and TAMs recruited by CCL2. [ABSTRACT FROM AUTHOR]

Aberrant interleukin-1 beta (IL-1β) expression is associated with cancer development, metastasis, and poor prognosis. Here, we have investigated the regulatory mechanism of IL-1β expression, and the inhibitory effect of zerumbone (ZER) on IL-1β expression and IL-1β-induced signatures, including cell invasion and signaling activation in triple negative breast cancer (TNBC) cells. The basal IL-1β and cell invasiveness levels were significantly higher in TNBC cells, compared with non-TNBC cells. The invasiveness of TNBC cells was also increased following IL-1β treatment. In contrast, the invasiveness of TNBC cells was decreased following IL-1 receptor antagonist (IL-1RA) treatment. Additionally, the basal IL-1β level and the invasiveness of TNBC cells were decreased by Bay11-7085. In contrast, overexpression of NF-κB (p65) caused an increase in IL-1β expression in TNBC cells. Our results showed that treatment with ZER decreased the basal IL-1β expression level, and the phosphorylation level of NF-κB, in TNBC cells. Furthermore, we found that ZER completely suppressed IL-1β-induced NF-κB phosphorylation, but did not suppress IL-1β-induced Akt phosphorylation, in TNBC cells. Our results also demonstrate that IL-1β-induced cell invasion is suppressed by ZER in TNBC cells. Taken together, we demonstrated that IL-1β expression is regulated by the NF-κB-dependent pathway, and that elevated IL-1β is directly influencing the invasiveness of TNBC cells. ZER down-regulates IL-1β expression through the inhibition of NF-κB activity, and then suppresses cell invasiveness of TNBC. [ABSTRACT FROM AUTHOR]