Expression of nuclear insulin receptor substrate 1 in breast cancer.
BACKGROUND
Insulin receptor substrate 1 (IRS-1), a cytoplasmic protein transmitting signals from the insulin and insulin-like growth factor 1 receptors, has been implicated in breast cancer. Previously, it was reported that IRS-1 can be translocated to the nucleus and modulate oestrogen receptor alpha (ERalpha) activity in vitro. However, the expression of nuclear IRS-1 in breast cancer biopsy specimens has never been examined.


OBJECTIVE
To assess whether nuclear IRS-1 is present in breast cancer and non-cancer mammary epithelium, and whether it correlates with other markers, especially ERalpha. Parallel studies were carried out for the expression of cytoplasmatic IRS-1.


METHODS
IRS-1 and ERalpha expression was assessed by immunohistochemical analysis. Data were evaluated using Pearson's correlation, linear regression and receiver operating characteristic analysis.


RESULTS
Median nuclear IRS-1 expression was found to be low in normal mammary epithelial cells (1.6%) and high in benign tumours (20.5%), ductal grade 2 carcinoma (11.0%) and lobular carcinoma (approximately 30%). Median ERalpha expression in normal epithelium, benign tumours, ductal cancer grade 2 and 3, and lobular cancer grade 2 and 3 were 10.5, 20.5, 65.0, 0.0, 80 and 15%, respectively. Nuclear IRS-1 and ERalpha positively correlated in ductal cancer (p<0.001) and benign tumours (p<0.01), but were not associated in lobular cancer and normal mammary epithelium. In ductal carcinoma, both nuclear IRS-1 and ERalpha negatively correlated with tumour grade, size, mitotic index and lymph node involvement. Cytoplasmic IRS-1 was expressed in all specimens and positively correlated with ERalpha in ductal cancer.


CONCLUSIONS
A positive association between nuclear IRS-1 and ERalpha is a characteristic for ductal breast cancer and marks a more differentiated, non-metastatic phenotype.
Sisci
Diego
D
Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Italy.
Morelli
Catia
C
Garofalo
Cecilia
C
Romeo
Francesco
F
Morabito
Lucio
L
Casaburi
Filomena
F
Middea
Emilia
E
Cascio
Sandra
S
Brunelli
Elvira
E
Andò
Sebastiano
S
Surmacz
Eva
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D055504:Insulin Receptor Substrate Proteins; D042361:Mammary Glands, Human / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*
D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins