Abstract B66: Benzo(a)pyrene increases expression of HPV oncoproteins: A potential co-factor for increased cervical cancer among American Indian women living in the Northern Plains

Introduction: Cervical cancer remains one of the most common and deadly cancers in women worldwide. There is a significant health disparity in the incidence and mortality of cervical cancer between American Indian and Caucasian women, especially for American Indian women residing in the Northern Plains. The development of cervical cancer is closely associated with persistent infection with a high risk genotype of HPV. Additionally, exposure to cigarette smoke is also a risk factor for cervical cancer. Our previous and current studies indicate that American Indian women living in the Northern Plains have a high rate of both HPV infection and exposure to cigarette smoke. While smoking is known to increase the risk of developing cervical cancer, the molecular interactions between HPV and smoke carcinogens are not well known. The purpose of this study was to determine the molecular effects of benzo-a-pyrene (BaP) (a carcinogen in cigarette smoke) on the expression of HPV oncoproteins. Methods: The effects of BaP on HPV associated molecular events was determined using cervical cancer cell lines. Following BaP exposure in either an acute or extended treatment protocol, the levels of HPV oncoproteins, activation of NFkB and AP-1 cell signaling pathways and intracellular reactive oxygen species (ROS) were determined using a combination of techniques including flow cytometry, immunofluorescence and immunoblotting. Cervical cancer cells were also treated with curcumin, a natural anti-cancer and chemopreventive compound. Results: In cervical cancer cells, exposure to BaP increased the expression of HPV oncoproteins in both acute and extended treatment protocols. BaP exposure also increased activation of NFkB and increased levels of ROS. To address the mechanism of increased HPV E7 protein expression, we assessed the ability of BaP to activate AP1 signaling. The AP1 family of transcription factors (including c-Fos) is known to induce transcription of HPV E6/E7 through binding to the Upstream Regulatory Region (URR). We detected an increase in the amount of AP1 (c-Fos) in the nucleus of cervical cancer cells exposed to BaP, suggesting that BaP may increase HPV oncoprotein expression through modulation of AP1. Interestingly, BaP9s increase in HPV oncoprotein expression was inhibited by curcumin treatment, likely through curcumin9s inhibition of AP-1 and NFkB pathways. Conclusion: Taken together this data imply that a high prevalence of HPV infection and a high exposure rate to BaP may synergize to increase the incidence and mortality of cervical cancer in American Indian women residing in the Northern Plains. Additionally, we have also identified curcumin as a potential compound that may be effective in preventing and/or treating cervical cancer. Increased cervical cancer screening is warranted for American Indian women living in the Northern Plains and additional steps, such as the use of the HPV vaccine and use of dietary agents, such as curcumin, may also be helpful to effectively decrease the health disparity associated with cervical cancer in American Indian women. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B66.