Adeno-associated virus type 2 infection of nude mouse human breast cancer xenograft induces necrotic death and inhibits tumor growth

Samina Alam, Brian S. Bowser, Mohd Israr, Michael J. Conway, Craig Meyers

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Abstract

We have previously reported that infection with the non-pathogenic, tumor suppressive, wild-type adeno-associated virus type 2 (AAV2) inhibited proliferation of breast cancer-derived lines representing both weakly invasive (MCF-7 and MDA-MB-468), as well as aggressive (MDA-MB-231) cancer types. AAV2-induced death occurred via targeting pathways of apoptosis and necrosis. In contrast, normal human mammary epithelial cells were unaffected upon AAV2 infection. The current study characterizes AAV2 infection and subsequent death of the highly aggressive, triple-negative (ER-/PR-/HER2-) MDA-MB-435 cell line derived from metastatic human breast carcinoma. Monolayer MDA-MB-435 cultures infected with AAV2 underwent complete apoptotic cell death characterized by activation of caspases -7, -8, and -9 and PARP cleavage. Death was further correlated with active AAV2 genome replication and differential expression of viral non-structural proteins Rep78 and Rep52. Cell death coincided with increased entry into S and G2 phases, upregulated expression of the proliferation markers Ki-67 and the monomeric form of c-Myc. Expression of the p16INK4, p27KIP1, p21WAF1, and p53 tumor suppressors was downregulated, indicating marked S phase progression, but sharply contrasted with hypo-phosphorylated pRb. In parallel, MDA-MB-435 breast tumor xenografts which received intratumoral injections of AAV2 were growth retarded, displayed extensive areas of necrosis, and stained positively for c-Myc as well as cleaved caspase-8. Therefore, AAV2 induced death of MDA-MB-435 xenografts was modulated through activation of caspaseregulated death pathways in relation to signals for cell cycle controls. Our findings provide foundational studies for development of novel AAV2 based therapeutics for treating aggressive, triple-negative breast cancer types.

Original languageEnglish (US)
Pages (from-to)1013-1028
Number of pages16
JournalCancer Biology and Therapy
Volume15
Issue number8
DOIs
Publication statusPublished - Aug 2014

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

@article{d120c16314ad4a67a956460b42da988c,
title = "Adeno-associated virus type 2 infection of nude mouse human breast cancer xenograft induces necrotic death and inhibits tumor growth",
abstract = "We have previously reported that infection with the non-pathogenic, tumor suppressive, wild-type adeno-associated virus type 2 (AAV2) inhibited proliferation of breast cancer-derived lines representing both weakly invasive (MCF-7 and MDA-MB-468), as well as aggressive (MDA-MB-231) cancer types. AAV2-induced death occurred via targeting pathways of apoptosis and necrosis. In contrast, normal human mammary epithelial cells were unaffected upon AAV2 infection. The current study characterizes AAV2 infection and subsequent death of the highly aggressive, triple-negative (ER-/PR-/HER2-) MDA-MB-435 cell line derived from metastatic human breast carcinoma. Monolayer MDA-MB-435 cultures infected with AAV2 underwent complete apoptotic cell death characterized by activation of caspases -7, -8, and -9 and PARP cleavage. Death was further correlated with active AAV2 genome replication and differential expression of viral non-structural proteins Rep78 and Rep52. Cell death coincided with increased entry into S and G2 phases, upregulated expression of the proliferation markers Ki-67 and the monomeric form of c-Myc. Expression of the p16INK4, p27KIP1, p21WAF1, and p53 tumor suppressors was downregulated, indicating marked S phase progression, but sharply contrasted with hypo-phosphorylated pRb. In parallel, MDA-MB-435 breast tumor xenografts which received intratumoral injections of AAV2 were growth retarded, displayed extensive areas of necrosis, and stained positively for c-Myc as well as cleaved caspase-8. Therefore, AAV2 induced death of MDA-MB-435 xenografts was modulated through activation of caspaseregulated death pathways in relation to signals for cell cycle controls. Our findings provide foundational studies for development of novel AAV2 based therapeutics for treating aggressive, triple-negative breast cancer types.",
author = "Samina Alam and Bowser, {Brian S.} and Mohd Israr and Conway, {Michael J.} and Craig Meyers",
year = "2014",
month = "8",
doi = "10.4161/cbt.29172",
language = "English (US)",
volume = "15",
pages = "1013--1028",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
publisher = "Landes Bioscience",
number = "8",

}