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

Abstract

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. Copyright © 2005 American Association for Cancer Research.