Abstract
Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.
Highlights
Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved
We show that IBC tumors mobilize distinct subsets of inflammatory cells locally and systemically, and demonstrate a key role of CCL2 secreted at very high levels in recruiting macrophages into tumors and thereby facilitating tumor growth and metastasis
The A3250 breast carcinoma cell line was established from a primary tumor of a patient with triple negative IBC, as previously described for other A series lines[15]
Summary
Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. We describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. Clinical symptoms include skin redness, an orange-peel appearance (peau d’orange) and swelling, making it initially challenging to distinguish from non-cancerous inflammatory diseases of the breast, as these tumors grow diffusely rather than as palpable nodules Another prominent feature of IBC is the presence of tumor emboli in dermal lymphatic vessels[4]. Diagnosis of IBC is made based on biopsy confirming the presence of cancer cells either in dermal lymphatics or in the breast parenchyma associated with clinical detection of inflammation[5,6] These distinct clinical and histopathological features suggest unique molecular drivers of the IBC phenotype. We show that IBC tumors mobilize distinct subsets of inflammatory cells locally and systemically, and demonstrate a key role of CCL2 secreted at very high levels in recruiting macrophages into tumors and thereby facilitating tumor growth and metastasis
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