title: Transcriptional targeting modalities in breast cancer gene therapy using adenovirus vectors controlled by alpha-lactalbumin promoter.
abstract: 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.
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Huanling
authors.initials: H
authors.lastname: Gao
authors.forename: Edyta
authors.initials: E
authors.lastname: Vieth
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Bae
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Raikwar
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gardner
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hutchins
authors.forename: Dale
authors.initials: D
authors.lastname: VanderPutten
authors.forename: Chinghai
authors.initials: C
authors.lastname: Kao
authors.forename: Meei-Huey
authors.initials: MH
authors.lastname: Jeng
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000472:pathogenicity; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007768:Lactalbumin / Q000235:genetics*; D008297:Male; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014774:Virulence; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D017931:DNA Primers; D007768:Lactalbumin