Dataset Information

Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression.

ABSTRACT: Ductal carcinoma in situ (DCIS) is the most common type of pre-invasive breast cancer diagnosed in women. Because the majority of DCIS cases are unlikely to progress to invasive breast cancer, many women are over-treated for DCIS. By understanding the molecular basis of early stage breast cancer progression, we may identify better prognostic factors and design treatments tailored specifically to the predicted outcome of DCIS. Chemokines are small soluble molecules with complex roles in inflammation and cancer progression. Previously, we demonstrated that CCL2/CCR2 chemokine signaling in breast cancer cell lines regulated growth and invasion through p42/44MAPK and SMAD3 dependent mechanisms. Here, we sought to determine the clinical and functional relevance of CCL2/CCR2 signaling proteins to DCIS progression. Through immunostaining analysis of DCIS and IDC tissues, we show that expression of CCL2, CCR2, phospho-SMAD3 and phospho-p42/44MAPK correlate with IDC. Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we show that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK. These studies demonstrate that increased CCL2/CCR2 signaling in breast tissues is associated with DCIS progression, and could be a signature to predict the likelihood of DCIS progression to IDC.

SUBMITTER: Fang WB

PROVIDER: S-EPMC8062684 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression.

Fang Wei Bin WB Sofia Acevedo Diana D Smart Curtis C Zinda Brandon B Alissa Nadia N Warren Kyle K Fraga Garth G Huang Li-Ching LC Shyr Yu Y Li Wei W Xie Lu L Staggs Vincent V Hong Yan Y Behbod Fariba F Cheng Nikki N

Scientific reports 20210422 1

Ductal carcinoma in situ (DCIS) is the most common type of pre-invasive breast cancer diagnosed in women. Because the majority of DCIS cases are unlikely to progress to invasive breast cancer, many women are over-treated for DCIS. By understanding the molecular basis of early stage breast cancer progression, we may identify better prognostic factors and design treatments tailored specifically to the predicted outcome of DCIS. Chemokines are small soluble molecules with complex roles in inflammat ...[more]

PMID: 33888841

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Project description:Objective: The present study investigated the roles and underlying mechanism of CCL2/CCR2 axis in the interactions between tumor cells and tumor-associated macrophages (TAMs) during the progression of salivary adenoid cystic carcinoma (SACC). Methods: Immunohistochemical staining and survival analysis were performed to study the correlation and clinical value of CD68, CD163, CCL2, and CCR2 expression in SACC cases. CCL2 silencing by RNA interference and CCR2 blocking by CCR2 specific antagonist (RS504393) were performed. ELISA, qRT-PCR, western blot, immunofluorescence, flow cytometry, CCK8, scratch wound healing, and transwell assays were used to explore the functional roles and possible mechanism of CCL2/CCR2 axis in the interactions between SACC cells and TAMs. The effects of targeting TAMs by blocking the CCL2/CCR2 axis were investigated in a xenograft mice model with SACC cells. Results: The high infiltration of TAMs marked by CD68 and high infiltration of M2 TAMs marked by CD163 were significantly correlated with the expression of CCL2 and CCR2 in SACC tissues. Notably, the high infiltration of TAMs and the overexpression of CCL2 were obviously associated with the clinical progression and poor prognosis of SACC. SACC cells derived CCL2 could activate its receptor CCR2 expression in TAMs in vitro. The in vitro results further indicated that the SACC cells derived CCL2 was involved in the recruitment, M2 polarization, and GDNF expression of TAMs through the CCL2/CCR2 axis. Meanwhile, TAMs derived GDNF promoted the proliferation, migration, and invasion of SACC cells through the GDNF/p-RET pathway. Treating immunodeficient mice with the CCR2 antagonist (RS504393) greatly inhibited the infiltration of TAMs and the tumorigenicity of SACC cells. Conclusion: These new findings indicated that the CCL2/CCR2 axis promoted the progression of SACC cells via recruiting and reprogramming TAMs. Targeting TAMs by blocking the CCL2/CCR2 axis might be a prospective strategy for SACC therapy.

Dataset Information

Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression.

Publications

Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression.

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