In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction

Kenji Ohba; Koji Ichiyama; Misako Yajima; Nobuhiro Gemma; Masaru Nikaido; Qingqing Wu; PeiPei Chong; Seiichiro Mori; Rain Yamamoto; John Eu Li Wong; Naoki Yamamoto

doi:10.1371/journal.pone.0097787

In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction

PLoS One. 2014 May 23;9(5):e97787. doi: 10.1371/journal.pone.0097787. eCollection 2014.

Authors

Affiliations

¹ Infectious Disease program, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
² TOSHIBA Research & Development Center, TOSHIBA Corporation, Kawasaki, Kanagawa, Japan.
³ Materials and Devices Division, TOSHIBA Corporation, Minato-ku, Tokyo, Japan.
⁴ Infectious Disease program, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor Darul Ehsan, Malaysia.
⁵ Pathogen Genomics Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
⁶ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America.
⁷ Department of Hematology-Medical Oncology, National University Cancer Institute, the Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Abstract

High prevalence of infection with high-risk human papilloma virus (HPV) ranging from 25 to 100% (average 31%) was observed in breast cancer (BC) patients in Singapore using novel DNA chip technology. Early stage of BC demonstrated higher HPV positivity, and BC positive for estrogen receptor (ER) showed significantly higher HPV infection rate. This unique association of HPV with BC in vivo prompted us to investigate a possible involvement of HPV in early stages of breast carcinogenesis. Using normal breast epithelial cells stably transfected with HPV-18, we showed apparent upregulation of mRNA for the cytidine deaminase, APOBEC3B (A3B) which is reported to be a source of mutations in BC. HPV-induced A3B overexpression caused significant γH2AX focus formation, and DNA breaks which were cancelled by shRNA to HPV18 E6, E7 and A3B. These results strongly suggest an active involvement of HPV in the early stage of BC carcinogenesis via A3B induction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Breast Neoplasms / diagnosis
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Breast Neoplasms / virology*
Carcinogenesis*
Cell Transformation, Viral
Cytidine Deaminase / deficiency
Cytidine Deaminase / genetics
Cytidine Deaminase / metabolism*
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genomic Instability
HEK293 Cells
Humans
Mammary Glands, Human / metabolism
Mammary Glands, Human / pathology
Middle Aged
Minor Histocompatibility Antigens
Papillomaviridae / physiology*
Prognosis
Receptors, Estrogen / metabolism
Time Factors

Substances

Minor Histocompatibility Antigens
Receptors, Estrogen
APOBEC3B protein, human
Cytidine Deaminase

Grants and funding

This work was supported by NUS SoM Start-up Grant (R-182-000-160-733). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.