CCL20 induces migration and proliferation on breast epithelial cells

Abstract

The communication between the tumor cells and the surrounding cells helps drive the process of tumor progression. Since the microenvironment of breast cancer includes CCL20 chemokine, the purpose of this study was to determine whether CCL20 modulates the physiology of healthy breast epithelial cells in areas adjacent to the tumor. Therefore, primary cultures of mammary cells taken from normal peritumoral areas were used. We assessed that breast cells expressed CCR6 CCL20 receptor. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated by CCR6 and involved in CCL20-induced breast cell proliferation and migration. The binding of 10 ng/ml CCL20 to CCR6 induced cell migration whilst higher concentrations (from 15 to 25 ng/ml) led to cell proliferation. CCL20 controlled cell migration and MMP-9 expression by PKC-alpha that activated Src, which caused the activation of downstream Akt, JNK, and NF-kB pathways. Furthermore, higher CCL20 concentrations increased cycE and decreased p27Kip expression ending in enhanced cell proliferation. Cell proliferation occurred through PKC-epsilon activation that transactivated EGFR and ERK1/2/MAPK pathway. Although activated by different CCL20 concentrations, these pathways function in parallel and crosstalk to some extent, inasmuch as Akt activation was responsible for ERK1/2 nuclear translocation and enhanced the transcription of of c-fos and c-myc, involved in cell proliferation. In summary, tumor cells exchange signals with the surrounding healthy cells modifying the extracellular matrix through enzyme secretion; thus, CCL20 might be a factor involved in the ontogeny of breast carcinoma.

Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model

“…In contrast, with little tumor-killing effect, the low-dose PTX-responsive genes have been well proven to extensively participate in tumor progression [40][41][42][43]. For instance, our study revealed that lowdose PTX induced more than 2000-fold upregulation of CCL20, which has been identified as the potent promalignant factor in breast cancer [44,45]. More importantly, in clinical survey, this gene expression pattern shares similarities with that of patients with inflammatory breast cancers.…”

Cytoplasmic Localization of Proline, Glutamic Acid, Leucine-rich Protein 1 (PELP1) Induces Breast Epithelial Cell Migration through Up-regulation of Inhibitor of κB Kinase ɛ and Inflammatory Cross-talk with Macrophages

“…Interestingly, chemokine (C-C motif) receptor 6, the receptor for CCL20, was recently shown to be important for mouse mammary tumor virus-polyoma middle T-induced tumor formation and the recruitment of pro-tumorigenic macrophages. CCL20 has also been shown to enhance migration and proliferation of breast epithelial cells (49,50). The pro-inflammatory cytokine IL-1␤ has also been shown to play a role in breast cancer initiation and expression and has been linked to breast epithelial cell migration (51,52).…”

CCL20/CCR6 Signaling Regulates Bone Mass Accrual in Mice

“…In addition to its potential involvement in psoriasis, inflammatory bowel disease, and asthma, CCL20 has been reported to play a role in various cancers. (11,12) Exploring its potential involvement in renal cell carcinoma (RCC), we observed high levels of CCL20 in patient samples of RCC bone metastasis, which is classically associated with excessive bone resorption. Correspondingly, inflammatory chemokines of the MIP family have been identified as potential mediators of pathological bone loss where MIP-1a and MIP-1d have been shown to directly enhance osteoclast development.…”