Abstract B75: Benzo(a)pyrene exposure increases expression of HPV oncoproteins: A potential co-factor for increased cervical cancer among Northern Plains American Indian women.
Authors: Maher Diane M. , Bell Maria , Schaefer Amanda , O'Donnell Emmylu , Jaggi Meena , Chauhan Subhash 
Published: August 2014

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 residing on the Northern Plains. The development of cervical cancer is closely associated with persistent infection with high risk HPV genotypes. Additionally, exposure to cigarette smoke is also a risk factor for cervical cancer. Our studies indicate that Northern Plains American Indian women have a high rate of both HPV infection and smoking. Our studies also show that American Indian women who tested positive for HPV were more likely to have an abnormal PAP test than HPV positive Caucasian women. While smoking is known to increase the risk of developing cervical cancer, the molecular interactions between HPV and smoke carcinogens are not well known. Herein, we determine the cellular and molecular effects of benzo-a-pyrene (BaP) (a carcinogen in cigarette smoke) on HPV oncoprotein expression in cervical cancer cells and elucidate the role of the aryl hydrocarbon receptor (AhR) in this process.

Methods: The effects of BaP on HPV oncoproteins and AhR mediated molecular events was determined using cervical cancer cell line models using real time PCR, immunoblotting, immunostaining and flow cytometry analyses. Additionally, following knockdown of AhR, cervical cancer cells lines were exposed to BaP and the levels of HPV oncoproteins and Cytochrome P450 1A (CYP1A1) were determined by flow cytometry, immunofluorescence and immunoblotting. Cervical cancer cells were also treated with curcumin to inhibit HPV oncoprotein expression. The level of AhR activation in normal cervix and in cervical cancer tissues was also determined with immunohistochemical analysis.

Results: We show for the first time that exposure to Benzo-[a]-pyrene (BaP), a tobacco carcinogen, increases the expression of HPV E7 oncoprotein in both acute and extended treatment protocols. To address the mechanism of increased HPV E7 protein expression, we determined that BaP activates AhR in cervical cancer cells which may directly or indirectly increase HPV oncoprotein expression. AhR activation is increased in cervical cancer tissue compared to normal cervical epithelium. Importantly, curcumin, natural compound, attenuated the BaP induced increase in the expression of HPV E7 oncoprotein.

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. We have identified curcumin as a potent compound that may be effective in attenuating oncogenic HPV infection. However, increased cervical cancer screening is warranted in addition to HPV vaccine and use of dietary agents, such as curcumin, to effectively decrease the cervical cancer health disparity in Northern Plains American Indian women.

Citation Format: Diane M. Maher, Maria Bell, Amanda Schaefer, Emmylu O'Donnell, Meena Jaggi, Subhash Chauhan. Benzo(a)pyrene exposure increases expression of HPV oncoproteins: A potential co-factor for increased cervical cancer among Northern Plains American Indian women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B75.