Раковая наука и терапия

Induction of Differential Growth in vitro by High-risk Human Papillomavirus in Human Breast Cancer Cell Lines is Associated with Caspase Dysregulation

Abstract

Karl Kingsley, Jennifer Zuckerman, Morghan Davis, Matt Matteucci, Aubrey Knavel, Jacqueline Rinehart, Van Tran, Demian Woyciehowsky, Phillip Jenkins, Rui Yu, Dieu-Hoa Nguyen and Susan O’Malley

Introduction Many viruses have been associated with human breast cancers, including Epstein-Barr and Cytomegalovirus. New evidence has revealed the frequent presence of highrisk human papillomavirus (HPV) strains HPV16 and HPV18 in breast carcinoma biopsies. These findings raise the question of whether HPV may infect developing cancers and mediate their growth and development, as was recently observed with oral cancers. The goal of this study is to test the hypothesis that these high-risk HPV strains are sufficient to significantly alter phenotypes of already transformed human breast cancer cell lines. Materials and methods A series of in vitro experiments, including proliferation, adhesion and viability assays, were used to quantify the effects of HPV16 and HPV18 on the human breast cancer cell lines, T-47D and MCF7, following transient transfection with the full length HPV virus. Normal breast and fibroblast cell lines, MCF10A and Hs27, were used as noncancerous controls. Results HPV16 and HPV18 significantly inhibited proliferation and adhesion of T-47D cells, although viability was not affected. Differential effects on proliferation were observed in MCF7 cells; HPV16 inhibited proliferation, while HPV18 stimulated proliferation. No measurable effects in adhesion or viability in MCF7 cells were observed. The phenotypic changes in T-47D and MCF7 cells were associated with changes in mRNA expression of caspase-2,-3 and -8, but not p53 or GAPDH. No measurable changes in proliferation or viability were observed following HPV transfection in the normal human breast cell line, MCF10A, or the normal human fibroblast cell line, Hs27, although adhesion was differentially affected. Conclusions Although HPV is a primary cause of virtually all cervical cancers, it is found as a concomitant infection in many other tumors. While HPV may initiate carcinogenesis in these tumors, recent studies suggest HPV may also modulate the progression or malignancy process in already transformed cancers. Determining what effects HPV has on already transformed breast cancers may therefore become an important step towards understanding the factors that will lead to more effective treatment options for a significant proportion of breast cancer patients.