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Experimental Therapeutics

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 and J. Bruce Robertson
Carlos L. Arteaga
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Stephen D. Hurd
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Teresa C. Dugger
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Angela R. Winnier
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J. Bruce Robertson
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DOI:  Published September 1994
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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 α (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 µg/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-ΔCys-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-ΔCys-PE40 and other chimeric toxins using the same cellular target will address this possibility.

Footnotes

  • ↵1 Supported by a Research Associate Career Development award and Merit Review grant from the Department of Veteran Affairs and American Cancer Society Grant CB-2 (C. L. A.).

  • ↵2 To whom requests for reprints should be addressed, at Division of Medical Oncology, Vanderbilt University, 22nd Avenue South, 1956 TVC, Nashville, TN 37232-5536.

  • Received March 23, 1994.
  • Accepted June 28, 1994.
  • ©1994 American Association for Cancer Research.
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September 1994
Volume 54, Issue 17
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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 and J. Bruce Robertson
Cancer Res September 1 1994 (54) (17) 4703-4709;

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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 and J. Bruce Robertson
Cancer Res September 1 1994 (54) (17) 4703-4709;
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