Estrogen pathway and cervical carcinogenesis. (a) Estrogen pathway. Estrogen binds to its cytosolic/nuclear receptors (ERα and ERβ) and membrane receptor GPR30 to exert its functions. Estrogen binds to ERs in the cytoplasm and induces ER homo- or hetero-dimerization. Estrogen-bound ERs then translocate to the nucleus, where they activate or repress target genes by two different mechanisms: classical pathway: ER binds to ERE and modulates target genes, and non-classical pathway: ER binds to AP1 or Sp1 transcription factors associated with their recognition sites in enhancer elements and modifies their function. Estrogen also binds to the membraneous receptor GPR30, a member of the G-protein coupled receptor family, and rapidly transduces various signaling pathways including but not limited to phosphatidyl inositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and Ca²⁺ signaling (non-genomic pathway). (b) Progressive disease leading to cervical cancer. It is believed that the multipotent reserve cells present in the transformation zone of the cervix are the progenitor cell type for cervical cancer. High-risk HPVs (HR-HPVs), such as HPV-16, infect and persist in these cells, and promote their aberrant squamous differentiation, which leads to atypical squamous metaplasia (ASM). ASM can progress to cervical intraepithelial neoplasia (CIN) grade 1–3 and eventually cervical cancer. This progressive neoplastic disease process normally takes over a decade following initial HPV infection before culminating in frank cancer. In most women, cervical disease spontaneously resolves prior to the development of cervical cancer.

Model for synergy between HPV and estrogen in cervical cancer. The three HPV oncogenes E5, E6, and E7 contribute to varying degrees to the development of cervical cancer through their abilities to induce cell proliferation, inhibit cell death, abrogate cellular DNA damage responses, and induce genomic instability. Estrogen contributes to cervical cancer at least in part through its ERα-dependent induction of cell proliferation. HPV gene products can either enhance or suppress estrogen’s stimulation of ERα transcriptional activity. Estrogen can in turn activate expression of HPV oncogenes potentially through ERα or perhaps other means. The interplay between HPV and estrogen may contribute to the synergistic activities of these viral and cellular factors in causing cervical cancer. Disrupting the estrogen/ERα pathway provides a novel approach to preventing or treating cervical cancer, for example, through SERMs.

Requirement of ERα for genesis and persistence of cervical cancer. (a) Influence of ERα status on cervical disease in HPV transgenic mice. Shown is the worst disease state in the cervices of K14E7/ERα^+/+ (red; +) or K14E7/ERα^−/− (green; −) mice treated for 6 months with 17β-estradiol. Note the complete absence of disease in mice deficient for ERα as compared to the presence of high-grade dysplasia, CIN3 (33%), or cervical cancer (66%) in ERα-sufficient mice. Data taken from [21]. (b) Effectiveness of SERMs in treating cervical neoplasia in HPV transgenic mice. Shown is the worst disease state in the cervices of K14E6E7 mice treated with 17β-estradiol for 6 months to induce cervical cancer, then either left untreated (red; −) or treated with fulvestrant (green; F) or raloxifene (blue; R) for 1 month. Note the complete (100%) or near complete (92%) loss of disease in mice treated with raloxifene or flulvestrant, respectively, compared to the retention of CIN3 (21%) or cervical cancer (79%) in those mice not treated with a SERM. Data taken from [22].

Meta-analyses of risks of cervical cancer related to parity and oral contraceptive use. (a) Relative risks (RRs) of cervical cancer and corresponding 95% floating confidence intervals (FCIs) by number of full-term pregnancies (FTPs) stratified by age at first FTP [40]. Among parous women, there was an increased risk of cervical cancer with number of FTPs within each stratum of age at first FTP and vice versa. Compared to nulliparae, the risk for parity increased across strata of younger age at first FTP. ¹Conditioned on age and study or study centre. ²As in¹, and conditioned on age at first sexual intercourse and lifetime number of sexual partners. (b) Relative risk (RR) of cervical cancer, floating standard errors (FSEs) and corresponding floating confidence intervals (FCIs) in relation to time since last use within categories of duration of use of combined oral contraceptives [41]. For duration of use less than 5 years, there was no significant increase of cervical cancer risk, compared to never users, in any category of time since last use. For women who had used combined oral contraceptives for 5 or more years, the RR in current use was almost twice that of never users. By 10 or more years since last use, the risk was not significantly different from that in never users. ¹Conditioned on age and study centre. ²As in¹, and conditioned on age at first sexual intercourse, lifetime number of sexual partners, number of full-term pregnancies, smoking and screening status.