The Role of HPV and Hormone in Cervical Precancer and Cancer - Molecular Pathophysiology and Cell Biology of Disease and Treatment

Sep 22, 2026

Cervical cancer remains a major global health challenge despite HPV vaccination, screening, and treatment. Persistent high-risk HPV infection is necessary, yet only a small fraction progresses to malignancy, highlighting additional cofactors. This review summarizes evidence that estrogen signaling modifies HPV-driven carcinogenesis by enhancing genomic instability, immune evasion, and tumor progression through tumor microenvironment reprogramming, including stromal and immune cell estrogen receptor pathways.

LanguageEnglish

CategoryHealthcare

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Pages22

Reading Time55 min

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[http://doi.org/10.32604/or.2026.078219](http://doi.org/10.32604/or.2026.078219) REVIEW The Role of HPV and Hormone in Cervical Precancer and Cancer: Molecular Pathophysiology and Cell Biology of Disease and Treatment Pei-Yu Kao 1 , Jie-Hong Chen2 and Kuo-Hu Chen 1,3, * 1Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, New Taipei City, Taiwan 2School of Medicine, College of Medicine, MacKay Medical University, New Taipei City, Taiwan 3School of Medicine, Tzu-Chi University, Hualien, Taiwan *Corresponding Author: Kuo-Hu Chen. Email: [alexgfctw@yahoo.com.tw](alexgfctw@yahoo.com.tw) [Received: 26 December 2025](Received: 26 December 2025); [Accepted: 12 March 2026](Accepted: 12 March 2026); [Published: 21 May 2026](Published: 21 May 2026) ABSTRACT: Cervical cancer remains a major global health challenge despite advances in human papillomavirus (HPV) vaccination, screening, and treatment. Persistent infection with high-risk HPV types, particularly HPV16 and HPV18, is a necessary cause of cervical cancer; however, only a small fraction of infections progress to malignancy, indicating the importance of additional cofactors. Increasing evidence identifies estrogen signaling as a critical modifier of HPV-driven carcinogenesis. Estrogen acts synergistically with HPV oncogenes E6 and E7 to promote genomic instability, immune evasion, and tumor progression, largely through effects on the tumor microenvironment (TME) . This review aims to clarify and summarize current knowledge on the interplay between HPV biology, estrogen signaling, and the cervical cancer microenvironment, discussing HPV structure, life cycle, and mechanisms of oncogenesis including viral genome integration, disruption of tumor suppressor pathways, and induction of chromosomal instability. Particular emphasis is placed on estrogen receptor signaling, highlighting the shift from tumor cell–intrinsic estrogen receptor α (ERα) expression to a paracrine, stromal-driven mechanism during disease progression. Estrogen signaling in cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells fosters an immunosuppressive microenvironment that supports viral persistence and malignant transformation. Both classical genomic and rapid non-genomic estrogen pathways are discussed, as well as their roles in immune modulation and DNA damage responses. Furthermore, there is emerging evidence linking estrogen signaling to HPV-induced genomic instability through pathways involving G protein-coupled estrogen receptor 1 (GPER1), estrogen receptor α36 (ERα36), High Mobility Group AT-Hook 2 (HMGA2), and wings apart-like (WAPL) . Finally, thereview contextualizes these molecular insights within contemporary clinical management, summarizing standard treatments and recent advances in targeted and immunotherapies, including bevacizumab and pembrolizumab. Understanding estrogen-driven stromal–immune crosstalk in HPV-associated cervical carcinogenesis may uncover novel therapeutic opportunities. Integrating hormonal modulation with immunotherapy and other targeted strategies represents a promising avenue to improve outcomes, particularly in advanced and treatment-resistant disease. KEYWORDS: Cervical cancer; cervical precancer; human papillomavirus; estrogen signaling; tumor microenvironment 1 Introduction Globally, cervical cancer continues to be a public health burden despite decades of progress in screening, vaccination, and treatment. In 2020, an estimated 604,127 women were diagnosed with cervical cancer, and 341,831 died from the disease. A clear socioeconomic gradient is evident, with countries of low Human Copyright © 2026 The Authors. Published by Tech Science Press. This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dev

FAQs

Why is persistent high-risk HPV infection considered necessary for cervical cancer?

High-risk HPV persistence, especially HPV16 and HPV18, is described as a necessary cause of cervical cancer. However, most infections clear, so additional cofactors are required for progression.

How does estrogen signaling influence HPV-driven cervical carcinogenesis?

The review explains that estrogen acts synergistically with HPV oncogenes E6 and E7, promoting genomic instability, immune evasion, epithelial transformation, and tumor microenvironment remodeling.

Which tumor microenvironment cells are highlighted as estrogen-responsive during disease progression?

It emphasizes estrogen receptor α expression changes in tumor-associated stromal and immune cells, particularly cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells, fostering immunosuppression and supporting malignant transformation.

Sep 22, 2026

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