The breast-specific
antigen alpha-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
alpha-lactalbumin promoter, we investigated the activity of a 762-bp human
alpha-lactalbumin promoter.
Alpha-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
alpha-lactalbumin promoter, and in AdE1aALAE1b, expression of both E1a and E1b genes is under the control of a single
alpha-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
alpha-lactalbumin promoter. AdE1aALAE1b showed better
breast cancer-restricted replication than AdALAE1a, suggesting that a transcriptional targeting modality with
alpha-lactalbumin promoter controlling both E1a and E1b gene expression is superior to
alpha-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
alpha-lactalbumin promoter could regulate the replication of adenovirus to target
hormone-independent breast
cancers, suggesting that
alpha-lactalbumin promoter can be used to develop a novel therapeutic modality for
hormone-independent
breast cancer.