TY - JOUR
T1 - Molecular cloning of hMena (ENAH) and its splice variant hMena +11a
T2 - Epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines
AU - Di Modugno, Francesca
AU - DeMonte, Lucia
AU - Balsamo, Michele
AU - Bronzi, Giovanna
AU - Nicotra, Maria Rita
AU - Alessio, Massimo
AU - Jager, Elke
AU - Condeelis, John S.
AU - Santoni, Angela
AU - Natali, Pier Giorgio
AU - Nisticò, Paola
PY - 2007/3/15
Y1 - 2007/3/15
N2 - hMena (ENAH), an actin regulatory protein involved in the control of cell motility and adhesion, is modulated during human breast carcinogenesis. In fact, whereas undetectable in normal mammary epithelium, hMena becomes overexpressed in high-risk benign lesions and primary and metastatic tumors. In vivo, hMena overexpression correlates with the HER-2+/ER-/ Ki67 + unfavorable prognostic phenotype. In vitro, neuregulin-1 up-regulates whereas Herceptin treatment down-modulates hMena expression, suggesting that it may couple tyrosine kinase receptor signaling to the actin cytoskeleton. Herein, we report the cloning of hMena and of a splice variant, hMena+11a, which contains an additional exon corresponding to 21 amino acids located in the EVH2 domain, from a breast carcinoma cell line of epithelial phenotype. Whereas hMena overexpression consistently characterizes the transformed phenotype of tumor cells of different lineages, hMena +11a isoform is concomitantly present only in epithelial tumor cell lines. In breast cancer cell lines, epidermal growth factor (EGF) treatment promotes concomitant up-regulation of hMena and hMena+11a, resulting in an increase of the fraction of phosphorylated hMena+11a isoform only. hMena+11a overexpression and phosphorylation leads to increased p42/44 mitogen-activated protein kinase (MAPK) activation and cell proliferation as evidenced in hMena+11a-transfected breast cancer cell lines. On the contrary, hMena knockdown induces reduction of p42/44 MAPK phosphorylation and of the proliferative response to EGF. The present data provide new insight into the relevance of actin cytoskeleton regulatory proteins and, in particular, of hMena isoforms in coupling multiple signaling pathways involved in breast cancer.
AB - hMena (ENAH), an actin regulatory protein involved in the control of cell motility and adhesion, is modulated during human breast carcinogenesis. In fact, whereas undetectable in normal mammary epithelium, hMena becomes overexpressed in high-risk benign lesions and primary and metastatic tumors. In vivo, hMena overexpression correlates with the HER-2+/ER-/ Ki67 + unfavorable prognostic phenotype. In vitro, neuregulin-1 up-regulates whereas Herceptin treatment down-modulates hMena expression, suggesting that it may couple tyrosine kinase receptor signaling to the actin cytoskeleton. Herein, we report the cloning of hMena and of a splice variant, hMena+11a, which contains an additional exon corresponding to 21 amino acids located in the EVH2 domain, from a breast carcinoma cell line of epithelial phenotype. Whereas hMena overexpression consistently characterizes the transformed phenotype of tumor cells of different lineages, hMena +11a isoform is concomitantly present only in epithelial tumor cell lines. In breast cancer cell lines, epidermal growth factor (EGF) treatment promotes concomitant up-regulation of hMena and hMena+11a, resulting in an increase of the fraction of phosphorylated hMena+11a isoform only. hMena+11a overexpression and phosphorylation leads to increased p42/44 mitogen-activated protein kinase (MAPK) activation and cell proliferation as evidenced in hMena+11a-transfected breast cancer cell lines. On the contrary, hMena knockdown induces reduction of p42/44 MAPK phosphorylation and of the proliferative response to EGF. The present data provide new insight into the relevance of actin cytoskeleton regulatory proteins and, in particular, of hMena isoforms in coupling multiple signaling pathways involved in breast cancer.
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U2 - 10.1158/0008-5472.CAN-06-1997
DO - 10.1158/0008-5472.CAN-06-1997
M3 - Article
C2 - 17363586
AN - SCOPUS:34047257715
SN - 0008-5472
VL - 67
SP - 2657
EP - 2665
JO - Cancer research
JF - Cancer research
IS - 6
ER -