title: Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling.
abstract: To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1- CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ERα) to CxCa, ERα expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ERα in CIN and tumor cells was confirmed at the protein level. However, ERα expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ERα to FSP1+, CD34+, SMA- precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1-, CD34-, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERα mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ERα-induced stroma-tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ERα+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ERα in tumor-associated stromal fibroblasts.
authors.affiliation: Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53715; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53792; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Johan A
authors.initials: JA
authors.lastname: den Boon
authors.affiliation: Department of Immunology and Microbiology, University of Colorado Denver School of Medicine, Aurora, CO 80045;
authors.forename: Dohun
authors.initials: D
authors.lastname: Pyeon
authors.affiliation: Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Sophia S
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53715; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Mark
authors.initials: M
authors.lastname: Horswill
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892;
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892;
authors.forename: Mark
authors.initials: M
authors.lastname: Sherman
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Zuna
authors.affiliation: Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Zhishi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892;
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Rachel
authors.initials: R
authors.lastname: Pearson
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53792; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Meghan
authors.initials: M
authors.lastname: Schott
authors.affiliation: Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Lisa
authors.initials: L
authors.lastname: Chung
authors.affiliation: Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706;
authors.forename: Qiuling
authors.initials: Q
authors.lastname: He
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53792;
authors.forename: Paul
authors.initials: P
authors.lastname: Lambert
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;
authors.forename: Joan
authors.initials: J
authors.lastname: Walker
authors.affiliation: Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Newton
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892; ahlquist@wisc.edu wentzenn@mail.nih.gov.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53715; McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53792; Institute for Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706; ahlquist@wisc.edu wentzenn@mail.nih.gov.
authors.forename: Paul
authors.initials: P
authors.lastname: Ahlquist
mesh_terms: D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D030361:Papillomavirus Infections / Q000473:pathology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000209:etiology* / Q000821:virology
chemical_list: D047628:Estrogen Receptor alpha
keywords: HPV; cervical cancer; estrogen; stroma; tumor microenvironment