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Molecular Transitions from Papillomavirus Infection to Cervical

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Molecular Transitions from Papillomavirus Infection to Cervical Molecular transitions from papillomavirus infection to PNAS PLUS cervical precancer and cancer: Role of stromal estrogen receptor signaling Johan A. den Boona,b,c,1, Dohun Pyeond,1, Sophia S. Wange, Mark Horswilla,c, Mark Schiffmanf, Mark Shermanf, Rosemary E. Zunag, Zhishi Wangh, Stephen M. Hewittf, Rachel Pearsonc,i, Meghan Schottb,c, Lisa Chungh, Qiuling Heh, Paul Lambertb, Joan Walkerg, Michael A. Newtonh,j, Nicolas Wentzensenf,2, and Paul Ahlquista,b,c,i,2 aMorgridge Institute for Research, University of Wisconsin–Madison, Madison, WI 53715; bMcArdle Laboratory for Cancer Research, University of Wisconsin– Madison, Madison, WI 53792; cInstitute for Molecular Virology, University of Wisconsin–Madison, Madison, WI 53706; dDepartment of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045; eDivision of Cancer Etiology, Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010; fDivision of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892; gUniversity of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; hDepartment of Statistics, University of Wisconsin–Madison, Madison, WI 53706; iHoward Hughes Medical Institute, University of Wisconsin–Madison, Madison, WI 53706; and jDepartment of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, WI 53792 Contributed by Paul Ahlquist, May 13, 2015 (sent for review January 7, 2015; reviewed by Karl Münger and Lucia Pirisi-Creek) To study the multistep process of cervical cancer development, we invasive cancer. Although the key steps of the carcinogenic process, analyzed 128 frozen cervical samples spanning normalcy, increasingly HPV infection, progression to precancer, and invasion to cancer (3), severe cervical intraepithelial neoplasia (CIN1– CIN3), and cervical can- are widely accepted, the factors behind these transitions are not cer (CxCa) from multiple perspectives, revealing a cascade of progres- well-understood. Many established cervical cancer risk factors, such sive changes. Compared with normal tissue, expression of many DNA as young age at onset of sexual activity and a high number of sexual replication/repair and cell proliferation genes was increased in CIN1/ partners, are related to exposure to HPV. Risk factors that are CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. associated with progression from HPV infection to precancer in- The CIN3-to-CxCa transition showed metabolic shifts, including de- clude smoking and oral contraceptive use (15, 16). The exact role of MEDICAL SCIENCES creased expression of mitochondrial electron transport complex com- hormonal factors in progression to precancer and cancer is unclear. ponents and ribosomal protein genes. Significantly, despite clinical, Mouse models strongly support the continuing importance of es- epidemiological, and animal model results linking estrogen and es- trogen and estrogen receptor alpha (ERα) at all carcinogenic steps trogen receptor alpha (ERα) to CxCa, ERα expression declined >15- (17–19) but human data are limited, particularly regarding ERα. fold from normalcy to cancer, showing the strongest inverse correla- tion of any gene with the increasing expression of p16, a marker for Significance HPV-linked cancers. This drop in ERα in CIN and tumor cells was confirmed at the protein level. However, ERα expression in stromal Cervical cancer (CxCa) is the second most frequent cancer in cells continued throughout CxCa development. Our further studies women and the third leading cause of cancer death in women localized stromal ERα to FSP1+,CD34+,SMA− precursor fibrocytes worldwide. Our global analysis of gene expression in normal, adjacent to normal and precancerous CIN epithelium, and FSP1−, precancerous, and cancerous cervical tissue shows increased CD34−,SMA+ activated fibroblasts in CxCas. Moreover, rank corre- DNA replication/repair and cell proliferation followed by sub- lations with ERα mRNA identified IL-8, CXCL12, CXCL14, their recept- stantial metabolic shifts. We observed a dramatic, progressive ors, and other angiogenesis and immune cell infiltration and decrease in estrogen receptor alpha (ERα) in tumor progression, inflammatory factors as candidates for ERα-induced stroma–tumor and ranking specimens by estrogen-responsive gene expression signaling pathways. The results indicate that estrogen signaling in correlated remarkably with histopathology. Whereas ERα ex- cervical cancer has dramatic differences from ERα+ breast cancers, pression shuts off in tumor epithelium, stromal fibroblasts in and imply that estrogen signaling increasingly proceeds indirectly the microenvironment retain ERα, and the data indicate estro- through ERα in tumor-associated stromal fibroblasts. gen-related alteration of several candidate stroma–tumor sig- naling pathways. Our findings strongly support a role of cervical cancer | HPV | estrogen | tumor microenvironment | stroma stromal estrogen signaling in CxCa development with implica- tions for CxCa management and control. lobally, cervical cancer (CxCa) is the second most common > Gcancer in women, with 500,000 new cases each year, half of Author contributions: J.A.d.B., D.P., S.S.W., P.L., J.W., N.W., and P.A. designed research; which are ultimately fatal (1). In the developed world, routine CxCa J.A.d.B., D.P., M.H., S.M.H., R.P., and M. Schott performed research; J.A.d.B., M. Schiffman, screening for abnormal cervical cytology, human papillomavirus M. Sherman, R.E.Z., Z.W., L.C., Q.H., and M.A.N. analyzed data; and J.A.d.B., D.P., N.W., (HPV), or both (2) has strongly reduced CxCa incidence, dem- and P.A. wrote the paper. onstrating the value of recognizing and removing early neoplasms Reviewers: K.M., Tufts University School of Medicine; and L.P.-C., University of South Carolina. (3). Such screening programs present a rare opportunity to study the sequential molecular changes in the development of a human The authors declare no conflict of interest. cancer (4). Freely available online through the PNAS open access option. CxCa development is related to infection with high-risk onco- Data deposition: A complete set of Affymetrix CEL files and GC-RMA–normalized gene – expression values for all individual tissue specimens reported in this paper has been genic HPVs, most prominently HPV16 and HPV18 (5 7). HPV deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo oncoproteins E6 and E7 are best known for blocking tumor sup- (accession no. GSE63514). pressor functions of p53 and Rb, respectively, but have numerous 1J.A.d.B. and D.P. contributed equally to this work. – additional interaction partners (8 13). Most cervical HPV infections 2To whom correspondence may be addressed. Email: [email protected] or wentzenn@mail. are cleared (14), but in a fraction of cases persistent infections lead nih.gov. to increasingly severe grades of dysplasia (cervical intraepithelial This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. neoplasia grades 1, 2, and 3; CIN1, CIN2, CIN3) and ultimately to 1073/pnas.1509322112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1509322112 PNAS Early Edition | 1of10 Downloaded by guest on September 26, 2021 Defining the molecular changes associated with CxCa pro- Table 1. Rank correlations between microarray- and real-time gression should reveal underlying mechanisms and improve quantitative PCR–based gene expression CxCa risk assessment, diagnosis, prognosis, and treatment. Ac- Gene Correlation* P value cordingly, we analyzed genome-wide gene expression changes in 128 cryosectioned and laser capture microdissected (LCM) cer- AR 0.73 1.03E-12 vical tissue specimens, representing all clinically recognized CDKN2A 0.76 9.08E-14 stages of CxCa progression. The results revealed sequential CHEK1 0.57 4.96E-07 changes in DNA replication and repair and metabolic, signaling, CXCL14 0.79 1.78E-15 CXCR2 0.79 2.00E-15 and other pathways, whose nature and timing imply important α mechanistic principles underlying CxCa development. ESR1 (ER ) 0.79 1.11E-15 We show that dramatically decreasing levels of ERα (also FN1 0.56 7.22E-07 GREB1 0.81 2.22E-16 called ESR1) mRNA and its effects on expression of estrogen- IL-8 0.66 8.34E-10 responsive genes is closely associated with progression to CxCa. MTHFD1L 0.32 7.51E-03 Our immunohistochemistry and immunofluorescence results con- α’ MUC4 0.76 8.30E-14 firmed ER s decline in epithelial lesions and tumors at the protein PGR 0.76 3.13E-14 α level, whereas revealing sustained or elevated ER levels in stro- SOD2 0.51 9.79E-06 mal cells. These and other results indicate that in high-grade cer- VEGFA 0.55 9.12E-07 vical lesions and CxCa, estrogen signaling must largely proceed indirectly through activated fibroblasts in the stromal microenvi- *According to calculation model 4, as further explained in Dataset S3. ronment. These findings reveal major differences in the possible tumor-promoting effects of estrogen in CxCa and breast cancer, with corresponding clinical implications (16, 20, 21). normal (24), CIN1 (14), CIN2 (22), CIN3 (40), and cancers (28) (Dataset S1). Except for cervical cancer specimens with more Results than 80% tumor content, LCM was used to enrich samples for Gene Expression Measurement and Validation. The 128 cervical speci- epithelial content before gene expression analysis with full hu- mens were separated by histopathology
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