The cytoskeleton regulatory protein hMena (ENAH) is overexpressed in human benign breast lesions with high risk of transformation and human epidermal growth factor receptor-2-positive/hormonal receptor-negative tumors.
OBJECTIVE
hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2).


METHODS
hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors. Correlations with conventional pathologic and prognostic variables, such as proliferation index, hormonal receptor status, and HER-2 overexpression, were also evaluated. In vitro experiments were done to study the effect of neuregulin-1 and Herceptin treatments on hMena expression.


RESULTS
hMena protein is undetectable in normal breast and is weakly expressed in a small percentage of low-risk benign diseases (9%), but displays a progressive and significant increase of positivity in benign lesions at higher risk of transformation (slightly increased risk 43%; moderate increased risk 67%), in in situ (72%), invasive (93%), and metastatic breast cancer (91%). A significant direct correlation with tumor size (P = 0.04), proliferation index (P < 0.0001), and HER-2 overexpression (P < 0.0001) and an inverse relationship with estrogen (P = 0.036) and progesterone receptors (P = 0.001) are found in invasive carcinomas. In vitro experiments show that neuregulin-1 up-regulates, whereas Herceptin down-regulates, hMena expression.


CONCLUSIONS
Our data provide new insights into the relevance of actin-binding proteins in human breast carcinogenesis and indicate hMena overexpression as a surrogate indicator in breast disease management.
Laboratory of Experimental Chemotherapy, Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
Francesca
F
Di Modugno
Marcella
M
Mottolese
Anna
A
Di Benedetto
Andrea
A
Conidi
Flavia
F
Novelli
Letizia
L
Perracchio
Irene
I
Venturo
Claudio
C
Botti
Elke
E
Jager
Angela
A
Santoni
Pier Giorgio
PG
Natali
Paola
P
Nisticò
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D001940:Breast; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000556:secondary; D002291:Carcinoma, Papillary / Q000378:metabolism / Q000556:secondary; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D018299:Neoplasms, Ductal, Lobular, and Medullary / Q000378:metabolism / Q000556:secondary; D020890:Neuregulin-1 / Q000494:pharmacology; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012307:Risk Factors; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab