Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling

Johan A. Den Boon, Dohun Pyeon, Sophia S. Wang, Mark Horswill, Mark Schiffman, Mark E. Sherman, Rosemary E. Zuna, Zhishi Wang, Stephen M. Hewitt, Rachel Pearson, Meghan Schott, Lisa Chung, Qiuling He, Paul Lambert, Joan Walker, Michael A. Newton, Nicolas Wentzensen, Paul Ahlquist

Research output: Contribution to journalArticle

84 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E3255-E3264
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number25
DOIs
StatePublished - Jun 23 2015

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Papillomavirus Infections
Estrogen Receptor alpha
Uterine Cervical Neoplasms
Estrogen Receptors
Estrogens
Neoplasms
Genes
Cervical Intraepithelial Neoplasia
Ribosomal Proteins
Stromal Cells
Electron Transport
DNA Replication
Interleukin-8
DNA Repair
Epithelium
Animal Models
Fibroblasts
Cell Proliferation
Breast Neoplasms
Messenger RNA

Keywords

  • Cervical cancer
  • Estrogen
  • HPV
  • Stroma
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

Cite this

Molecular transitions from papillomavirus infection to cervical precancer and cancer : Role of stromal estrogen receptor signaling. / Den Boon, Johan A.; Pyeon, Dohun; Wang, Sophia S.; Horswill, Mark; Schiffman, Mark; Sherman, Mark E.; Zuna, Rosemary E.; Wang, Zhishi; Hewitt, Stephen M.; Pearson, Rachel; Schott, Meghan; Chung, Lisa; He, Qiuling; Lambert, Paul; Walker, Joan; Newton, Michael A.; Wentzensen, Nicolas; Ahlquist, Paul.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 25, 23.06.2015, p. E3255-E3264.

Research output: Contribution to journalArticle

Den Boon, JA, Pyeon, D, Wang, SS, Horswill, M, Schiffman, M, Sherman, ME, Zuna, RE, Wang, Z, Hewitt, SM, Pearson, R, Schott, M, Chung, L, He, Q, Lambert, P, Walker, J, Newton, MA, Wentzensen, N & Ahlquist, P 2015, 'Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 25, pp. E3255-E3264. https://doi.org/10.1073/pnas.1509322112
Den Boon, Johan A. ; Pyeon, Dohun ; Wang, Sophia S. ; Horswill, Mark ; Schiffman, Mark ; Sherman, Mark E. ; Zuna, Rosemary E. ; Wang, Zhishi ; Hewitt, Stephen M. ; Pearson, Rachel ; Schott, Meghan ; Chung, Lisa ; He, Qiuling ; Lambert, Paul ; Walker, Joan ; Newton, Michael A. ; Wentzensen, Nicolas ; Ahlquist, Paul. / Molecular transitions from papillomavirus infection to cervical precancer and cancer : Role of stromal estrogen receptor signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 25. pp. E3255-E3264.
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T2 - Role of stromal estrogen receptor signaling

AU - Den Boon, Johan A.

AU - Pyeon, Dohun

AU - Wang, Sophia S.

AU - Horswill, Mark

AU - Schiffman, Mark

AU - Sherman, Mark E.

AU - Zuna, Rosemary E.

AU - Wang, Zhishi

AU - Hewitt, Stephen M.

AU - Pearson, Rachel

AU - Schott, Meghan

AU - Chung, Lisa

AU - He, Qiuling

AU - Lambert, Paul

AU - Walker, Joan

AU - Newton, Michael A.

AU - Wentzensen, Nicolas

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N2 - 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.

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KW - Stroma

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