Abstract
Human breast carcinoma cell lines express high-affinity interleukin-4 receptors (IL-4R). We examined the expression and structure of these receptors on primary and cultured breast carcinoma cell lines and normal breast epithelial cells. We also tested the antitumor activity in vitro and in vivo of a fusion protein comprised of circular permuted IL-4 and truncated Pseudomonas exotoxin, termed IL-4(38-37)-PE38KDEL. Eight different primary cell cultures and cell lines of human breast carcinomas were examined for the expression of IL-4R by radiolabeled binding, reverse transcription polymerase chain reaction (RT-PCR) and Northern analyses, and subunit structure by crosslinking studies. The antitumor activity of IL-4 toxin was tested in vitro by cytotoxicity assays and in vivo in a xenograft model in immunodeficient animals. 125I-IL-4 specifically bound to primary cell cultures and cell lines with a Kd ranging between 0.2 and 1 nM. Breast tumor cells were found to express IL-4R beta and IL-13R alpha' chains, but not IL-2R gamma c chain. These cells were highly sensitive to the cytotoxic effect of IL-4(38-37)-PE38KDEL. The IC50 (concentration inhibiting protein synthesis by 50%) ranged between approximately 0.005-1.5 nM. A normal breast epithelial cell culture was not sensitive to the cytotoxic activity of IL-4(38-37)-PE38KDEL. MDA-MB231 human breast carcinoma cell line formed a rapidly growing tumor in nude mice. Intratumor and intraperitoneal administration of IL-4(38-37)-PE38KDEL caused a dose dependent regression of established tumors. A control toxin, anti-Tac(Fv)-PE38KDEL, targeted to the IL-2 receptor alpha chain did not cause regression of these tumors. These results suggest that IL-4(38-37)-PE38KDEL may be a useful agent for targeting of IL-4 receptor positive human breast carcinomas and further studies should be performed to explore fully its potential.
Highlights
Breast cancer is the most common malignancy in women, resulting in the second most frequent cause of cancer death among women in the United States [1]
We demonstrated by reconstitution experiments that a 60–70 kDa protein form of interleukin-13 receptor (IL13R) can substitute for Ͳc when mediating IL-4 signaling and, this chain forms a third subunit of the interleukin-4 receptors (IL-4R) system (IL-13RͰЈ termed as IL-13RͰ1) [18,21,27,28]
It is not known whether primary cell cultures of human breast carcinoma express IL-4R and if they do, whether these cells and breast cancer cell lines are susceptible to the cytotoxic activity of IL-4toxins
Summary
Breast cancer is the most common malignancy in women, resulting in the second most frequent cause of cancer death among women in the United States [1]. Heregulin-Pseudomonas exotoxin, which the ligand Heregulin binds to ErbB-2, ErbB-3 and ErbB-4 receptors, is connected to a truncated form of Pseudomonas exotoxin (PE) This cytotoxin is highly cytotoxic in vitro and in vivo to breast cancer cells that overexpress ErbB-4 or ErbB-2 plus ErbB-3 receptors [2]. A recombinant, humanized moncloclonal antiHer antibody (Herceptin) was able to significantly inhibit growth of breast cancer in an animal model and in the clinic [4] This antibody synergized with paclitaxel when mediating antitumor activity against breast tumor xenograft models. Herceptin was recently licensed by the U.S Food and Drug Administration (FDA) for the treatment of breast cancer These studies demonstrate that these classes of biotherapeutics can provide an additional mode of breast cancer therapy, their clinical benefits have yet to be completely explored. Results: 125I-IL-4 bound to primary cell cultures and cell lines with a Kd ranging between
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