Differential immunohistochemical detection of transforming growth factor α, amphiregulin and CRIPTO in human normal and malignant breast tissues

Abstract

The expression of growth factors, such as transforming growth factor a (TGFa), amphiregulin (AR) and CRIPTO, a type-I tyrosine-kinase growth factor receptor (erbB-2), and a tumor-suppressor gene (p53). that have been implicated in the development and/or the progression of breast cancer, was evaluated by immunohistochemistry in I00 human primary infiltrating breast carcinomas (IBC). AR and CRIPTO imrnunoreactivity was also assessed in 55 human breast ductal carcinomas in situ (DCIS). Within the I00 IBC, 80,50,73, 17, and 34 tumors expressed moderate to high levels of TGFol, AR, CRIPTO, erb6-2, and p53 respectively. In addition, AR and CRIPTO immunoreactivity were found in I I and in 26 out of 55 DCIS respectively. In contrast, only 4, 3, and 2 out of 10 normal mammary-gland samples were weakly positive for TGFol, AR, and CRIPTO expression, respectively, whereas none was positive for erbB-2 or p53. Within the I00 IBC, expression of erb6-2 significantly correlated with high histologic and nuclear grading, with high growth fraction, and with estrogen-receptor(ER)-and progesterone-receptor(PgR)-negative tumors. A statistically rignificant correlation was also observed between p53 expression and high histologic grading, high growth fraction, and PgRnegative tumors. In contrast, no significant correlations were found between TGFol, AR, and CRIPTO imrnunoreactivity and various clinicopathological parameters, with the exception of a positive correlation between TGFa and ER expression. These data demonstrate that TGFol, AR, and CRIPTO expression are significantly increased in malignant mammary epithelium relative to normal epithelium. In particular, the differential expression of CRIPTO may serve as a potential tumor marker for breast carcinogenesis.o 1996 Wilq-Liss, Inc.

Differential regulation of cell proliferation and protease secretion by epidermal growth factor and amphiregulin in tumoral versus normal breast epithelial cells

“…However, whereas a moderate stimulation of AR expression was induced by 10 Ϫ8 M EGF in normal mammary cells (210 ± 75% of control), a similar EGF concentration increased AR expression level to 980% and 550% of control in the breast cancer epithelial cell lines MDA-MB231 and MCF-7, respectively. These data are in agreement with reports demonstrating that the expression of some EGF-related growth factors including AR is significantly increased in malignant mammary epithelium relative to normal epithelium Panico et al, 1996). Gene transcription is dependent on the activation of specific transcription factors.…”

“…AR, which has been described as a potent stimulator of proliferation in a variety of cell types, is expressed by epithelial cells in a number of normal human tissues including the mammary gland (Li et al, 1992;Panico et al, 1996). Moreover, AR has been shown to act as an autocrine growth factor for normal human mammary epithelial cells in vitro (Li et al, 1992;Kenney et al, 1993; Normanno et al, 1994a, b) and its overexpression observed in human malignancies such as breast cancers has been suggested to be involved in tumoral cell growth disregulation (Normanno et al, 1994a, b;Visscher et al, 1997).…”

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

“…There is clear evidence for a role of amphiregulin in breast cancer initiation as well as progression (McBryan et al, 2008;Willmarth and Ethier, 2008). Amphiregulin is often overexpressed in mammary carcinoma (Qi et al, 1994) and generally higher in invasive breast carcinomas than in normal mammary epithelium (Panico et al, 1996).…”

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

“…AR and HB-EGF are upregulated in breast (LeJeune et al, 1993;Normanno et al, 1995;Salomon et al, 1995;Panico et al, 1996;Visscher et al, 1997), prostate (Bostwick et al, 2004), and gastric cancers (Cook et al, 1992;Kitadai et al, 1993;Ebert et al, 1994;Normanno et al, 1995) and keratinocytic tumors (Billings et al, 2003). Shedding of HB-EGF is a critical step in tumor formation (Miyamoto et al, 2004), and overexpression of AR promotes growth of keratinocytic tumors (Billings et al, 2003).…”