Expression of transforming growth factor α, amphiregulin and cripto-1 in human breast carcinomas

Cf, Qi; Ds, Liscia; Normanno, Nicola; Merlo, Giorgio R.; Johnson, Graham R.; Gullick, WJ; Ciardiello, Fortunato; Sendo, Toshiaki; Brandt, Ralf; N., Kim

doi:10.1038/bjc.1994.174

Cited by 122 publications

(105 citation statements)

References 45 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxiainducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-a protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…Measurements of mRNA expression of the EGF family of ligands showed that both cell lines expressed high levels of AREG and modest amounts of HB-EGF and TGF-a. The coexpression of two or more EGF-like growth factors frequently occurs in human carcinomas (Ciardiello et al, 1991;Qi et al, 1994;Normanno et al, 2001). Yano et al, 2004;TfeltHansen et al, 2005b).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice

et al. 2007

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The purpose of this study was to evaluate the role of the epidermal growth factor receptor (EGFR) in parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcaemia of malignancy (HHM), using two different human squamous-cell carcinoma (SCC) xenograft models. A randomised controlled study in which nude mice with RWGT2 and HARA xenografts received either placebo or gefitinib 200 mg kg À1 for 3 days after developing HHM. Effectiveness of therapy was evaluated by measuring plasma calcium and PTHrP, urine cyclic AMP/creatinine ratios, and tumour volumes. The study end point was at 78 h. The lung SCC lines, RWGT2 and HARA, expressed high levels of PTHrP mRNA as well as abundant EGFR protein, but very little erbB2 or erbB3. Both lines expressed high transcript levels for the EGFR ligand, amphiregulin (AREG), as well as, substantially lower levels of transforming growth factor-a (TGF-a), and heparin binding-epidermal growth factor (HB-EGF) mRNA. Parathyroid hormone-related protein gene expression in both lines was reduced 40 -80% after treatment with 1 mM of EGFR tyrosine kinase inhibitor PD153035 and precipitating antibodies to AREG. Gefitinib treatment of hypercalcaemic mice with RWGT2 and HARA xenografts resulted in a significant reduction of plasma total calcium concentrations by 78 h. Autocrine AREG stimulated the EGFR and increased PTHrP gene expression in the RWGT2 and HARA lung SCC lines. Inhibition of the EGFR pathway in two human SCC models of HHM by an anilinoquinazoline demonstrated that the EGFR tyrosine kinase is a potential target for antihypercalcaemic therapy.

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“…DISCUSSION Other than EGF or TGF-a, the role of additional EGF-related growth factors such as AR, heparin-binding EGF, or beta- cellulin in regulating the proliferation, differentiation, and transformation of mammary epithelial cells is relatively undefined (1,20). Like TGF-a, AR is expressed in both normal and transformed human mammary epithelial cells, in several human breast cancer cell lines, and in 40-80% of primary human breast carcinomas (11,13,14,18,19,21,22). Furthermore, both TGF-a and AR mRNA expression are induced after treatment with physiological, growth-promoting concentrations of 17p-estradiol in estrogen-responsive MCF-7 human breast cancer cells (18,23,24).…”

Section: Methodsmentioning

confidence: 99%

Amphiregulin as an autocrine growth factor for c-Ha-ras- and c-erbB-2-transformed human mammary epithelial cells.

Normanno

Selvam

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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Amphiregulin (AR), a member of the epidermal growth factor (EGF) family, was found to be as potent as EGF in stimulating the anchorage-dependent growth (ADG) of immortalized, nontransformed human mammary epithelial MCF-10A cells. MCF-10A cells transformed by either an activated human c-Ha-ras protooncogene (MCF-10A ras) or by overexpression of a nonactivated rat c-neu gene (MCF-10A neu) exhibited a 35% reduction in the response to AR in ADG when compared to MCF-10A cells, but AR was still as potent as EGF in these transformants. Exogenous AR exhibited only 15-20% of the activity of EGF in stimulating the anchorage-independent growth, a response that is normally dependent upon exogenous EGF, of the oncogene-transformed MCF-10A cells. MCF-10A cells express low levels of a 1.4-kb AR mRNA transcript, while MCF-10A ras and MCF-10A neu cells display a 15- to 30-fold increase in the levels of AR mRNA and endogenous AR protein as determined by Western blot analysis. Exogenous EGF was found to induced both the AR mRNA and protein in the MCF-10A parental and transformed cells. A 20-mer phosphorothioate antisense deoxyoligonucleotide complementary to the 5' sequence of AR mRNA was able to significantly reduce the levels of endogenous AR protein and to inhibit the EGF-stimulated ADG and anchorage-independent growth of MCF-10A ras and MCF-10A neu cells. These data suggest that AR may function as an EGF-dependent autocrine growth factor in mammary epithelial cells that have been transformed by either a point-mutated c-Ha-ras or c-neu.

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Expression of transforming growth factor α, amphiregulin and cripto-1 in human breast carcinomas

Abstract: Summary The expression of three epidermal growth factor (EGF)-related peptides, transforming growth factor a (TGF-a), amphiregulin (AR) and cripto-l (CR-1), was examined by immunocytochemistry (ICC)

Cited by 122 publications

References 45 publications

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

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

Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice

Amphiregulin as an autocrine growth factor for c-Ha-ras- and c-erbB-2-transformed human mammary epithelial cells.

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