Expression of Amphiregulin, Cripto-1, and Heregulin-Alpha in Human Breast-Cancer Cells

Normanno, Nicola; Qi, C. F.; Gullick, William J.; Persico, Graziella; Yarden, Yosef; Wen, Duanzhi; Plowman, Gregory D.; Kenney, Nicholas; Johnson, Gibbes R.; Kim, N.; Brandt, Ralf; Martínez-Lacaci, Isabel; Dickson, Robert B.; Salomon, David

doi:10.3892/ijo.2.6.903

Cited by 65 publications

(52 citation statements)

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“…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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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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“…For example, ER induces the expression of transcripts for both transforming growth factor a (TGFa) and amphiregulin (AR) (Saeki et al 1991, Normanno et al 1993. TGFa and AR are both able to bind and activate EGFR thus leading to activation of MAPK and AKT signaling (Salomon et al 1995).…”

Section: Mechanism Of Action Of Ermentioning

confidence: 99%

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Normanno

Maïo

Maio

et al. 2005

Endocr Relat Cancer

257

224

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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

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“…38 Finally, CR-1 expression is elevated in a majority of mouse and human mammary tumors relative to noninvolved mammary epithelium. 7,17,18,20 In breast hyperplasia, ductal carcinoma in situ (DCIS) and invasive carcinomas, the degree of apoptosis has been shown to be correlated with increased malignancy. 3,43 It is therefore conceivable that CR-1 may be one factor that is contributing to the elevated apoptotic index in these lesions since CR-1 expression can first be detected in hyperplasias in different transgenic mice that eventually develop mammary tumors and in human DCIS.…”

Section: Discussionmentioning

confidence: 99%

Cripto-1 induces apoptosis in HC-11 mouse mammary epithelial cells

Santis

Martínez-Lacaci²,

Bianco³

et al. 2000

Cell Death Differ

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Cripto-1 (CR-1) is an epidermal growth factor (EGF)-related protein. CR-1 can inhibit b-casein and whey acidic protein expression in mouse mammary epithelial cells. The present study demonstrates that CR-1 can induce apoptosis in HC-11 mouse mammary epithelial cells, as measured by bisbenzimide stained nuclei, TUNEL assay and cell death ELISA. Apoptosis could be observed after 2 days of exposure of confluent HC-11 cells to CR-1 in the absence of the survival factors EGF and insulin, with maximum apoptosis occurring at 3 days. A reduction in poly(ADP-ribose) polymerase (PARP) expression and an increase in b-catenin cleavage was found after 18 h of exposure to CR-1 suggesting that apoptosis was preceded by the induction of a caspase activity since the caspase inhibitor ZFAD.FMK could block the CR-1-induced reduction in PARP expression and CR-1-induced apoptosis. CR-1 was found to increase the expression of caspase-3-like protease. Although, the levels of p27 kip1 and p21Bax did not change after exposure to CR-1 for 18 h, the levels of Bcl-x L became undetectable. These studies suggest that CR-1 promotes apoptosis by mediating the induction of caspase-3-like protease and downregulating the expression of Bcl-x L .

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Expression of Amphiregulin, Cripto-1, and Heregulin-Alpha in Human Breast-Cancer Cells

Cited by 65 publications

References 0 publications

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

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

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Cripto-1 induces apoptosis in HC-11 mouse mammary epithelial cells

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