Epidermal Growth Factor Receptors in Human Breast Carcinoma Cells

A Potential Selective Target for Transforming Growth Factor α-Pseudomonas Exotoxin 40 Fusion Protein

Carlos L. Arteaga, Stephen D. Hurd, Teresa C. Dugger, Angela R. Winnier, J. Bruce Robertson

Research output: Contribution to journalArticle

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Abstract

Epidermal growth factor (EGF) receptors are expressed in high levels by some poor prognosis breast tumors. We have examined the cytotoxic effect of the tumor growth factor a (TGFα)-δCys-Pseudomonas exotoxin (PE40) recombinant fusion protein on normal and tumorigenic human breast epithelial cells in vitro and in vivo. The MDA-468, MDA-231, BT-20, and MCF-7ADR estrogen receptor-negative, EGF receptor-rich breast cancer lines were exquisitely sensitive in vitro to TGFα-ΔCys-PE40 with a 50% inhibitory concentration of <0.02 nM. The estrogen receptor-positive, low EGF receptor MCF-7, ZR75-1, and T47D cells were less sensitive to the fusion toxin with a 50% inhibitory concentration of <0.2 nM. The nontumorigenic cell lines 184,184A1, and 184B5 were relatively resistant to TGFα-ΔCys-PE40 despite exhibiting high levels of EGF receptors. Continuous i.p. administration of TGFα-δCys-PE40 via an osmotic minipump at a dose of 0.4 ug/g/day over 7 days inhibited MDA-468, MA-231, and BT-20 but not MCF-7 tumor growth in female athymic mice. Host tissue toxicity was not observed with this dose of TGFα-ACys-PE40. Mixed MDA-468/MCF-7 tumors were established in nude mice after coinoculation of both cell types in estrogen-supplemented animals. EGF receptor immunohistochemistry and immunoblot procedures indicated that TGFα-PE40 eliminated the MDA-468 cells while sparing the adjacent MCF-7 cells. By immunoblot, EGF receptors were consistently more abundant in tumor tissue than in adjacent nontumor tissue from the same mastectomy specimen (n = 7). These data support the notion that EGF receptors can be selectively targeted in human breast cancer cells for the delivery of antitumor agents. Further clinical studies with TGFα-ACys-PE40 and other chimeric toxins using the same cellular target will address this possibility.

Original languageEnglish (US)
Pages (from-to)4703-4709
Number of pages7
JournalCancer Research
Volume54
Issue number17
StatePublished - Jan 1 1994

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Exotoxins
Transforming Growth Factors
Pseudomonas
Breast Neoplasms
Intercellular Signaling Peptides and Proteins
Neoplasms
Proteins
Epidermal Growth Factor Receptor
Nude Mice
Estrogen Receptors
Inhibitory Concentration 50
ErbB Receptors
Recombinant Fusion Proteins
Immunotoxins
Mastectomy
MCF-7 Cells
Antineoplastic Agents
Estrogens
Breast
Epithelial Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Epidermal Growth Factor Receptors in Human Breast Carcinoma Cells : A Potential Selective Target for Transforming Growth Factor α-Pseudomonas Exotoxin 40 Fusion Protein. / Arteaga, Carlos L.; Hurd, Stephen D.; Dugger, Teresa C.; Winnier, Angela R.; Robertson, J. Bruce.

In: Cancer Research, Vol. 54, No. 17, 01.01.1994, p. 4703-4709.

Research output: Contribution to journalArticle

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abstract = "Epidermal growth factor (EGF) receptors are expressed in high levels by some poor prognosis breast tumors. We have examined the cytotoxic effect of the tumor growth factor a (TGFα)-δCys-Pseudomonas exotoxin (PE40) recombinant fusion protein on normal and tumorigenic human breast epithelial cells in vitro and in vivo. The MDA-468, MDA-231, BT-20, and MCF-7ADR estrogen receptor-negative, EGF receptor-rich breast cancer lines were exquisitely sensitive in vitro to TGFα-ΔCys-PE40 with a 50{\%} inhibitory concentration of <0.02 nM. The estrogen receptor-positive, low EGF receptor MCF-7, ZR75-1, and T47D cells were less sensitive to the fusion toxin with a 50{\%} inhibitory concentration of <0.2 nM. The nontumorigenic cell lines 184,184A1, and 184B5 were relatively resistant to TGFα-ΔCys-PE40 despite exhibiting high levels of EGF receptors. Continuous i.p. administration of TGFα-δCys-PE40 via an osmotic minipump at a dose of 0.4 ug/g/day over 7 days inhibited MDA-468, MA-231, and BT-20 but not MCF-7 tumor growth in female athymic mice. Host tissue toxicity was not observed with this dose of TGFα-ACys-PE40. Mixed MDA-468/MCF-7 tumors were established in nude mice after coinoculation of both cell types in estrogen-supplemented animals. EGF receptor immunohistochemistry and immunoblot procedures indicated that TGFα-PE40 eliminated the MDA-468 cells while sparing the adjacent MCF-7 cells. By immunoblot, EGF receptors were consistently more abundant in tumor tissue than in adjacent nontumor tissue from the same mastectomy specimen (n = 7). These data support the notion that EGF receptors can be selectively targeted in human breast cancer cells for the delivery of antitumor agents. Further clinical studies with TGFα-ACys-PE40 and other chimeric toxins using the same cellular target will address this possibility.",
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