The Functional Effect of an Amphiregulin Autocrine Loop on Inflammatory Breast Cancer Progression

The epidermal growth factor (EGF) family ligand amphiregulin (AR) has been associated with breast cancer. We demonstrate that EGF-independent SUM149 breast cancer cells are synthesizing and secreting AR. MCF10A human mammary epithelial cells made to over express AR (MCF10A AR) are also EGF-independe...

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Bibliographic Details
Main Authors: Willmarth, Nicole E, Ethier, Stephen P
Format: Report
Language:English
Subjects:
AMPHIREGULIN
AUTOCRINE LOOP
Biochemistry
BREAST CANCER
COLON CANCER
EPIDERMAL GROWTH FACTOR RECEPTOR
ESTROGENS
INFLAMMATORY BREAST CANCER
LIGANDS
MAMMARY GLANDS
Medicine and Medical Research
OVEREXPRESSION
PANCREATIC CANCER
PROTEINS
TYROSINE
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Summary:The epidermal growth factor (EGF) family ligand amphiregulin (AR) has been associated with breast cancer. We demonstrate that EGF-independent SUM149 breast cancer cells are synthesizing and secreting AR. MCF10A human mammary epithelial cells made to over express AR (MCF10A AR) are also EGF-independent for growth. Treatment with the pan-erbB inhibitor CI1033 and the anti-EGFR antibody C225 demonstrated that ligand mediated activation of EGFR is required for SUM149 cell proliferation. AR neutralizing antibody reduced both SUM149 EGFR activity and cell proliferation confirming that an AR autocrine loop is required for mitogenesis. EGFR tyrosine phosphorylation was dramatically decreased in both SUM149 and MCF10A AR cells after inhibition of AR cleavage indicating that an AR autocrine loop is strictly dependent on AR cleavage in culture. However a juxtacrine assay where fixed SUM149 cells and MCF10A AR cells were overlain on top of EGF starved MCF10A cells showed that the AR membrane precursor can activate EGFR. SUM149 cells MCF10A AR cells and MCF10A cells growing in exogenous AR were all considerably more invasive and motile than MCF10A cells grown in EGF. Moreover AR upregulates genes involved in motility and invasion suggesting AR contributes to breast cancer progression. The original document contains color images.