Transcriptional targeting modalities in breast cancer gene therapy using adenovirus vectors controlled by α-lactalbumin promoter

• Published in: Molecular cancer therapeutics Vol. 4; no. 12; pp. 1850 - 1859
• Main Authors: Li, Xiong, Zhang, Jie, Gao, Huanling, Vieth, Edyta, Bae, Kyung-Hee, Zhang, Yan-Ping, Lee, Sang-Jin, Raikwar, Sudhanshu, Gardner, Thomas A, Hutchins, Gary D, VanderPutten, Dale, Kao, Chinghai, Jeng, Meei-Huey
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.12.2005
• Subjects: adenoviral vectors; Adenoviridae - genetics; Adenoviridae - pathogenicity; Adenovirus; Adenovirus E1A Proteins - genetics; Adenovirus E1B Proteins - genetics; Animals; Apoptosis - genetics; Base Sequence; Blotting, Western; breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - therapy; Cell Line, Tumor; conditional replicative adenovirus; DNA Primers; Female; gene therapy; Genetic Therapy; Genetic Vectors; human α-lactalbumin; Humans; Lactalbumin - genetics; Male; Mammary Glands, Human - metabolism; Mice; Mice, Nude; Promoter Regions, Genetic; Prostatic Neoplasms - genetics; Reverse Transcriptase Polymerase Chain Reaction; tissue-restricted replicative adenovirus; tissue-specific promoter; Virulence; Virus Replication
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-05-0167

The breast-specific antigen α-lactalbumin is expressed in >60% of breast cancer tissues. To evaluate the effect of gene therapy for breast cancer by controlling adenovirus replication with human α-lactalbumin promoter, we investigated the activity of a 762-bp human α-lactalbumin promoter. α-Lactalbumin promoter showed significantly higher activity in MDA-MB-435S and T47D breast cancer cells than in normal breast cell lines or other tumor cell lines. We then developed two novel breast cancer–restricted replicative adenoviruses, AdALAE1a and AdE1aALAE1b. In AdALAE1a, expression of adenoviral E1a gene is under the control of α-lactalbumin promoter, and in AdE1aALAE1b, expression of both E1a and E1b genes is under the control of a single α-lactalbumin promoter. Both breast cancer–restricted replicative adenoviruses showed viral replication efficiency and tumor cell-killing capability similar to wild-type adenovirus in MDA-MB-435S and T47D cells. The replication efficiency and tumor cell-killing capability of both viruses were attenuated significantly in cells that did not support α-lactalbumin promoter. AdE1aALAE1b showed better breast cancer–restricted replication than AdALAE1a, suggesting that a transcriptional targeting modality with α-lactalbumin promoter controlling both E1a and E1b gene expression is superior to α-lactalbumin promoter controlling only E1a gene expression. Importantly, we found that AdE1aALAE1b could be used to target hormone-independent breast tumors in vivo by inhibiting the growth of MDA-MB-435S s.c. tumors. These data showed that α-lactalbumin promoter could regulate the replication of adenovirus to target hormone-independent breast cancers, suggesting that α-lactalbumin promoter can be used to develop a novel therapeutic modality for hormone-independent breast cancer. [Mol Cancer Ther 2005;4(12):1850–9]