Interleukin-22 Mediates the Chemotactic Migration of Breast Cancer Cells and Macrophage Infiltration of the Bone Microenvironment by Potentiating S1P/SIPR Signaling

The interleukin-22 (IL-22) signaling pathway is well known to be involved in the progression of various cancer types but its role in bone metastatic breast cancer remains unclear. We demonstrate using human GEO profiling that bone metastatic breast cancer displays elevated interleukin-22 receptor 1 (IL-22R1) and sphingosine-1-phosphate receptor 1 (S1PR1) expression. Importantly, IL-22 stimuli promoted the expression of IL-22R1 and S1PR1 in aggressive MDA-MB-231 breast cancer cells. IL-22 treatment also increased sphingosine-1-phosphate production in mesenchymal stem cells (MSCs) and induced the sphingosine-1-phosphate (S1P)-mediated chemotactic migration of MDA-MB-231 cells. This effect was inhibited by an S1P antagonist. In addition to the S1PR1 axis, IL-22 stimulated the expression of matrix metalloproteinase-9 (MMP-9), thereby promoting breast cancer cell invasion. Moreover, IL-22 induced IL22R1 and S1PR1 expression in macrophages, myeloid cell, and MCP1 expression in MSCs to facilitate macrophage infiltration. Immunohistochemistry indicated that IL-22R1 and S1PR1 are overexpressed in invasive malignant breast cancers and that this correlates with the MMP-9 levels. Collectively, our present results indicate a potential role of IL-22 in driving the metastasis of breast cancers into the bone microenvironment through the IL22R1-S1PR1 axis.

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Effect of mTOR inhibition on sensitivity of triple-negative breast cancer cells to epidermal growth factor inhibition

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1055 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1055-1055 ◽

Cited By ~ 1

Author(s):

T. Liu ◽

R. Yacoub ◽

T. Graham ◽

L. Yang ◽

M. Tighiouart ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Triple Negative ◽

Metastatic Breast ◽

Mtor Inhibitors ◽

Egfr Inhibitors ◽

Breast Cancers ◽

Mtor Inhibition

1055 Background: The outcome for patients with triple negative (TN) cancers is poor at least in part because of a lack of targeted therapies. Although 50% of TN breast cancers over-express EGFR, the use of EGFR inhibitors as single agents in patients with unselected and TN metastatic breast cancers has produced disappointing results. Likewise, mTOR inhibitors have modest activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated that EGFR inhibitors in combination with rapamycin (RAPA) decrease cell survival, increase apoptosis, and are synergistic in TN breast cancer cells, compared to any of the agents alone (AACR 2008). We, therefore, evaluated the combination of mTOR and EGFR inhibition in vivo. Methods: Athymic mice were inoculated with TN (MDA-MB-231) breast cancer cells. One week after cell inoculation, mice were treated with vehicle, lapatinib 75mg/kg by mouth daily, RAPA 3mg/kg IP biweekly, or the combination. After 4 weeks of treatment, mice were sacrificed and tumors were assessed for target proteins by Western blotting and immunohistochemistry Results: The combination of RAPA and lapatinib resulted in a significant decrease in TN breast tumor volume (76 mm3), compared to rapamycin alone (133 mm3, p = 0.01), lapatinib alone (183 mm3, p < 0.0001) or control (188 mm3, p = 0.005). Neither lapatinib nor RAPA alone inhibited tumor growth significantly compared to control (p > 0.05). Interestingly, in contrast to our findings in vitro, the increase in pAkt noted in RAPA treated tumors was not decreased by lapatinib, despite the significant decrease in tumor size in tumors treated with the combination. Conclusions: These studies demonstrate that the combination of mTOR inhibition and lapatinib significantly inhibit TN breast cancer growth, compared with either agent alone. Given the lack of targeted therapies in TN breast cancers, these data support the possibility that mTOR inhibition can sensitize TN breast cancers to EGFR inhibitors. A clinical trial evaluating the combination of lapatinib and RAD001 as second-line therapy for TN metastatic breast cancer is planned. [Table: see text]

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