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. Author manuscript; available in PMC: 2022 Dec 17.
Published in final edited form as: Essays Biochem. 2021 Dec 17;65(6):941–950. doi: 10.1042/EBC20200175

Functional Roles of Female Sex Hormones and Their Nuclear Receptors in Cervical Cancer

Seoung-Ae Lee 1, Seunghan Baik 1, Sang-Hyuk Chung 1,*
PMCID: PMC8935983  NIHMSID: NIHMS1785192  PMID: 34156060

Abstract

There has been little progress for several decades in modalities to treat cervical cancer. While the cervix is a hormone-sensitive tissue, physiologic roles of estrogen receptor α (ERα), progesterone receptor (PR), and their ligands in this tissue are poorly understood. It has hampered critical assessments of data in early epidemiologic and clinical studies for cervical cancer. Experimental evidence obtained from studies using mouse models has provided new insights into the molecular mechanism of ERα and PR in cervical cancer. In a mouse model expressing human papillomavirus (HPV) oncogenes, exogenous estrogen promotes cervical cancer through stromal ERα. In the same mouse model, genetic ablation of PR promotes cervical carcinogenesis without exogenous estrogen. Medroxyprogesterone acetate, a PR-activating drug, regresses cervical cancer in the mouse model. These results support that ERα and PR play opposite roles in cervical cancer. They further support that ERα inhibition and PR activation may be translated into valuable treatment for a subset of cervical cancers.

Keywords: cervical cancer, estrogen, progesterone, ERα, PR, HPV, mouse model

Cervical cancer is the third most frequent cancer and the third leading cause of cancer death in women worldwide, with age-standardized rates of 569.8 cases and 311.4 deaths per 100,000 women [1]. More than 85% of cases represent squamous cell carcinomas, and the remainder is adenocarcinomas and rare neuroendocrine carcinomas [2]. This review focuses on the mechanisms relevant to squamous cell carcinomas. The primary etiologic factor for all types of cervical cancer is human papillomavirus (HPV). While the Papanicolaou (Pap) test and HPV vaccines prevent cervical cancer effectively, they are not readily available or affordable to women in underdeveloped/developing countries and women of low socioeconomic status in developed countries [3–6]. Also, women at high risk are not aware of the link between HPV and cervical cancer [7]. Furthermore, social or religious issues hinder universal vaccination [8]. Current therapies for cervical cancer are decades-old surgery, radiation, and chemotherapy, which are ineffective for treating advanced and recurrent diseases. A targeted therapy would improve the survival of cervical cancer patients.

Human Papillomavirus and Cervical Cancer

More than 200 different types of HPV are identified and classified into cutaneous and mucosal types depending on their tissue tropism [9, 10]. Mucosal types are further divided into low-risk and high-risk types. Low-risk HPVs are associated with benign lesions such as genital warts and laryngeal papillomas [11]. High-risk HPVs promote various cancers, among which cervical cancer is most prominent. Among more than a dozen high-risk types, HPV16 is responsible for approximately 60% of cervical cancer cases [12]. HPV16 encodes eight genes, including E5, E6, and E7 oncogenes [9]. While E5 is tumorigenic in vivo in an epidermal growth factor receptor-dependent manner [13], it is not expressed in approximately 40% of cervical cancer due to its deletion during viral genome integration into the cellular chromosome [14]. On the contrary, E6 and E7 are always expressed in HPV-induced cervical cancers and necessary for their continued growth [12]. The mechanism of E6 and E7, including the inactivation of p53 and pRb, respectively, has been extensively discussed in other reviews [15, 16]. The expression of E6 and E7 fails to transform primary rodent cells and human keratinocytes in vitro [17–19]. Also, it is estimated that cervical cancer occurs in less than 0.1% of HPV-infected women [4, 20]. Precancer lesions called cervical intraepithelial neoplasia (CIN) often regresses without any interventions [21]. These observations suggest that, in addition to HPV, other cofactors are necessary to develop cervical cancer.

Female Sex Hormones in Cervical Cancer

While most carcinomas increase with age, cervical cancer incidence in unscreened populations plateaus at 40–45 years of age [22]. This age pattern is similar to breast cancer, which is mainly estrogen-dependent [23]. Reanalyses of data on HPV-infected women have shown that cervical cancer risk is significantly higher in women who have used oral contraceptives for longer than 5 years than in never-users [24, 25]. However, the risk has returned to that of never-users when women have stopped using oral contraceptives for 10 or more years [24]. Women who have had seven or more full-term pregnancies starting at 17 years or younger have three times higher risk of developing cervical cancer than nulliparous women [26].

While these observations implicate female sex hormones, epidemiological studies looking at the association of estrogen and progesterone signaling with cervical cancer have been inconclusive. For example, randomized trials of hormone replacement therapy (HRT) are underpowered because HRT is predominantly used for postmenopausal women who are at low risk of cervical cancer (i.e., cervical cancer incidence is too low in study subjects) [27–29]. Prospective and retrospective studies evaluating the efficacy of selective ER modulators (SERMs) in preventing and treating breast cancer and osteoporosis have collected data for other gynecological diseases such as cervical cancer. However, the caveat mentioned above makes it difficult to use such data. A couple of case-control studies have argued that the use of medroxyprogesterone acetate (MPA, synthetic progesterone used as injectable contraceptive) does not change cervical cancer risk [30, 31]. Other studies have concluded that the use of MPA increases the risk of cervical cancer [32–34]. However, none of these studies have considered the infection by high-risk HPVs necessary for cervical cancer. More limitations and weaknesses of these studies have been discussed in previous reviews [27, 35].

Estrogen, Progesterone, and Their Nuclear Receptors

Estrogen binds to estrogen receptor α (ERα), estrogen receptor β (ERβ), and G-protein-coupled estrogen receptor (GPER). Progesterone binds to progesterone receptor (PR), membrane progesterone receptors (mPRs), and progesterone receptor membrane components (PGRMCs). ERα, ERβ, and PR are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. They have been successfully targeted for the treatment of various diseases, including cancer [36]. GPER, mPRs, and PGRMCs have transmembrane domains and localize primarily at the plasma membrane. These membrane-associated hormone receptors will not be discussed here because studies examining their roles in cervical cancer are scarce.

During hormonal cycles in humans and rodents, an estrogen surge results in various physiological changes (e.g., cell proliferation) in the female reproductive tracts, including the cervix [37]. The following progesterone surge reverses these changes [37]. While the estrogen surge increases PR expression through ERα in the cervix, the PR activity remains minimal because progesterone levels are low during estrogen surges (Figure 1). Estrogen levels drop subsequently, leading to decreased PR levels, but PR is activated as the ligand level increases during a progesterone surge (Figure 1). ERβ expression increases in the human cervix at term pregnancy, but its function in the cervix is poorly understood [38]. ERβ is undetectable in the mouse cervix and dispensable for the regulation of PR expression [39, 40]. In the breast, ERα and ERβ have pro- and anti-tumorigenic activities, respectively [41]. Compared to nuclear ERs, the roles of PR in epithelial cell proliferation are characterized less well. The PGR gene codes for PR-A and PR-B isoforms via alternative promoter usage. While PR-A and PR-B are identical except for additional 164 amino acids at the N-terminus in PR-B, progesterone-induced anti-inflammatory responses of uterine myometrial cells are mediated by PR-B and inhibited by PR-A [42, 43]. Therefore, both aberrant hormonal balance and perturbed expression ratios of these nuclear receptors may contribute to the pathogenesis of cervical cancer (Figure 1). Here, we will discuss the roles of ERα and PR in cervical carcinogenesis based on observations from mouse models of cervical cancer.

Figure. 1.

Figure. 1

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Dynamic activities promoting and suppressing cervical cancer during hormonal cycles During sexual cycles in women and mouse, estrogen (E) and progesterone (P) surge in turn. In a high E condition, pro-tumorigenic activity of ERα is greater than anti-cancer activity of PR. It should be noted that PR activity is low under this condition although its expression level is high. In a high P condition, tumor-suppressive activity of PR is predominant although PR levels decline. Thicker arrows/lines indicate dominant activities. H, human; M, mouse.

Estrogen-induced Cervical Carcinogenesis in Mouse Models

K14HPV16 single and K14E6/E7 double transgenic mice have been used to study HPV-induced cancers. The K14HPV16 single transgenic mouse contains a transgene allele composed of the KRT14 promoter and the entire HPV16 early region (Figure 2A) [44]. This mouse expresses E6 and E7, but it is unclear whether other early genes are expressed [44, 45]. The K14E6/E7 double transgenic mouse has K14E6 and K14E7 transgene alleles that express HPV16 E6 and E7, respectively (Figure 2B). Although E6 and E7 inactivate p53 and pRb pathways in the anus, cervix, and oral cavity of these mice, the transgenic mice do not develop overt tumors spontaneously [45–47]. It is consistent with the notion that HPV alone is not sufficient to promote cancers.

Figure. 2.

Figure. 2

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Schematics of HPV16 oncogne-expressing alleles (A) The K14HPV16 allele is composed of human keratin 14 (KRT14) promoter and HPV16 early region. It is unclear whether E1, E2, E4, and E5 are expressed. (B) K14E6 and K14E7 alleles have a translation termination linker (TTL) in E7 and E6 open reading frame, respectively. (C) Structures of mouse and human female reproductive tracts are illustrated. The transformation zone is indicated by purple boxes. Locations of cervical cancer in mouse models and human are indicated by colored lines. Note that figures are not drawn to scale. tg, transgenic.

The requirement of estrogen for cervical carcinogenesis has been initially demonstrated in K14HPV16 transgenic mice [48]. When they are treated with drug pellets slowly releasing 50 μg of estrogen over 60 days (i.e., 0.83 μg/day) for 6 months, 91% of mice have cervical cancer [49]. Serum estrogen levels in these mice are in a picomolar range and lower than those in mice at estrus [49], which is similar to those during the normal menstrual cycle in women [50]. Notably, 48% of cervical cancers develop in the endocervical transformation zone where the squamocolumnar junction moves [49]. Most cervical cancers occur in this anatomic location in women (Figure 2C). The same estrogen treatment regimen has promoted cervical cancer in K16E6/E7 double transgenic (95%) and K14E7 single transgenic mice (80%), but not in K14E6 single transgenic mice [45]. A longer estrogen treatment (9 months) has promoted cervical cancer in 41% of K14E6 mice [46]. These results indicate that E7 is more potent in promoting cervical cancer than E6. Estrogen also has promoted cervical cancer in a mouse papillomavirus infection model [51]. This mouse model has allowed the characterization of immune responses to E6 and E7 oncoproteins [52]. Also, unlike the transgenic mouse models, it recapitulates the situation that viral oncogene-expressing cells are surrounded by normal cells. However, cervical cancer does not occur in the endocervical transformation zone where most cervical cancers arise (Figure 2C). It is probably due to the limited access of the virus to the anatomical site because it is localized far away from the mouse vaginal cavity where viruses are inoculated (Figure 2C). In these mouse models, the cervical neoplastic disease progresses from low-grade to high-grade CIN and culminates in invasive cancer, recapitulating the multistage carcinogenesis in women [45, 49, 51]. The expression patterns of several biomarkers (e.g., p16, cyclin E, and Mcm7) are similar to those of human cervical cancer [45, 51, 53]. While these features demonstrate the relevance to human cervical cancer, it is a weakness that cancers are microscopic and non-metastatic. Nonetheless, studies using these mouse models have provided new insights into the role of ERα and PR in the development and growth of cervical cancer.

Cell Type-specific Roles of ERα in Cervical Carcinogenesis

In the mouse uterus and vagina, stromal ERα is necessary and sufficient for estrogen-induced epithelial cell proliferation [54, 55]. Cervical epithelial and stromal cells express ERα in both human and mouse. However, ERα is expressed in cancer-associated stromal cells but not in cervical cancer cells in women [56, 57]. These observations have raised a possibility that stromal ERα is essential for cervical carcinogenesis in women. The estrogen treatment has failed to promote any cervical neoplastic diseases in K14E7 mice with a germline knockout of Esr1, demonstrating that ERα is necessary for estrogen-induced cervical cancer [58]. A treatment with exogenous estrogen has promoted cervical cancer in K14E7 mice with the specific deletion of Esr1 in the cervical epithelium [40]. On the contrary, a temporal deletion of stromal ERα has regressed CIN and prevented estrogen-induced cervical cancer in K14E7 mice [59]. These results have demonstrated that stromal ERα rather than epithelial ERα is crucial for the development of cervical cancer. They also support a hypothesis that ERα promotes cervical cancer through a paracrine mechanism (Figure 3). The identification of a paracrine factor and its receptor mediating the pro-tumorigenic function of stromal ERα is warranted. In this regard, several dozens of extracellular proteins in cervical stroma have been identified in K14E6/K14E7 double transgenic mice [60]. While they could contribute to cervical cancer, it is unclear whether they are directly regulated by E2 and stromal ERα because untreated control mice have not been ovariectomized (i.e., endogenous E2 is present). In addition, their differential regulation could be the consequence of cancer because comparisons have been made between cancer-bearing and disease-free mice. For example, CXCL1 and CXCL5 are upregulated in a coculture of cancer cells and fibroblasts compared to a coculture of normal epithelial cells and fibroblasts in the absence of E2 treatment [60]. Regarding ERα-regulated paracrine factor-coding genes, estrogen and ERα promote development and carcinogenesis in the rodent mammary gland by upregulating amphiregulin, an epidermal growth factor receptor ligand [61, 62]. Estrogen upregulates insulin-like growth factor-1 (IGF-1) and activates IGF-1 receptor, which is required for estrogen/ERα-induced epithelial cell proliferation in the murine uterus [63, 64].

Figure. 3.

Figure. 3

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Potential drug targets for cervical cancer (A) ERα-inhibiting drugs may be effetive in treating cervical cancer by blocking the expression of cancer-promoting secretory factors in cancer stroma. If neoplastic cells are PR-positive, progestins may be effective in preventing and treating cervical cancer. Cancer-promoting factors and activities are shown in blue. Cancer-suppressing factors and activitities are shown in red. Note that epithelial ERα is shown in purple because it may have dual functions. CIN, cervical intraepithelial neoplasia; E, estrogen; P, progesterone. (B) Representative H&E images of cervical tissues from differentially treated mice are shown. Similar images have been shown in references [67,73]. Cervical cancer-bearing K14E6/K14E7 mice were treated with vehicle, raloxifene, or MPA. Raloxifene and MPA clear cervical cancer and induce the hypoplastic epithelium. MPA also results in epithelial cells with clear cytoplasm, indicative of mucinification (see the arrow). Dotted lines separate stroma from cancer and epithelium; scale bar: 25 μm.

Although estrogen promoted CIN and cervical cancer in all epithelial ERα-deficient K14E7 mice described above, cancer incidence in these mice is significantly lower than epithelial ERα-intact K14E7 control mice [40]. These results suggest that epithelial ERα contributes to the development of CIN but not to its progression to cancer. Unlike normal cervical epithelial cells in humans, they do not express ERα in epithelial ERα-deleted K14E7 mice [40]. A new mouse model allowing a temporal deletion of Esr1 in dysplastic cells is warranted. The knockdown of ERα increases the invasion of cervical cancer cells in vivo, and its overexpression decreases it [65]. It is consistent with the observation that ERα expression is absent or lower in cervical cancer cells than dysplastic cells [56, 65]. These observations raise a possibility that epithelial ERα promotes CIN but inhibits its progression to carcinoma by preventing the invasion into the stroma. If correct, epithelial ERα has both pro- and anti-cervical cancer activities depending on the disease stage.

PR as a Tumor Suppressor in Cervical Cancer

An estrogen surge results in hormone levels similar to those in the HPV transgenic mouse treated with exogenous estrogen [49]. Why is exogenous estrogen required for cervical carcinogenesis then? Treatment with MPA regresses cervical cancer in the HPV transgenic mouse model, suggesting that PR activation suppresses cervical cancer [66, 67]. Exogenous estrogen promotes cervical cancer similarly in K14E7 mice with and without the Pgr germline knockout [67]. However, K14E7 mice with the deletion of epithelial Pgr develop cervical cancer at high penetrance without exogenous estrogen treatment [68]. While Pgr germline knockout mice are at continuous diestrus, epithelial Pgr knockout mice cycle normally [68, 69]. Chronic estrogen treatment keeps mice at an estrus-like state at which progesterone levels remain low [49]. In other words, progesterone-mediated suppression of cervical cancer is absent, and thus the Pgr knockout has little effect on cervical carcinogenesis under the estrogen treatment condition. These observations support that pro-tumorigenic activities of endogenous estrogen are canceled out by anti-tumorigenic actions of progesterone in cycling mice (Figure 1). The deletion of one Pgr allele in the epithelium has promoted spontaneous cervical cancer as efficiently as the deletion of both Pgr alleles [68]. It is less likely that CIN3 lesions co-expressing ERα and PR progress to invasive cancer in women [70]. These results support that if estrogen levels are high, a decreased expression of PR or the lack of progesterone surges increases the risk of cervical cancer in HPV-infected women. Because ERα upregulates PR expression, this notion is consistent with the observation that ERα expression decreases in cervical cancer (i.e., PR decreases) [39]. High PR levels are associated with better overall survival in premenopausal cervical cancer patients but not in postmenopausal patients [68]. These results strongly support that PR is a tumor suppressor in cervical cancer (Figure 3). One of common features of polycystic ovary syndrome (PCOS) is infrequent ovulation (i.e., fewer progesterone surges than the healthy), and thus estrogen levels remain high longer in these patients [71, 72]. PCOS patients with HPV infections may be at a higher risk of developing cervical cancer.

Targeting ERα and PR to Prevent and Treat Cervical Cancer

The inhibition of stromal ERα with SERMs and selective ER degraders (SERDs) and activation of PR with progestins hold the translational value (Figure 3A). Indeed, fulvestrant (SERD) and raloxifene (SERM) are effective in preventing and treating cervical cancer in the HPV transgenic mouse model [73]. However, any SERDs will induce menopausal symptoms (it is significant because most cervical cancer patients are premenopausal). Also, it is unclear which SERM inhibits ERα in the human cervical stroma. Cervical cancer recurs after raloxifene therapy in the HPV transgenic mouse model even in the absence of exogenous E2, but recurrent cancers are still responsive to raloxifene [74]. MPA prevents and regresses cervical cancer in the mouse model [67, 75]. MPA also induces hypoplasia like raloxifene and mucinification evidenced by cells with clear cytoplasm (Figure 3B) [66, 67]. However, a minor fraction of CIN is resistant to MPA, and recurrence is frequent after stopping the treatment [66, 75]. In addition, recurrent cervical cancers are resistant to MPA even though they express PR [66]. The mechanism of MPA resistance should be determined.

Concluding Remarks and Outstanding Questions

While mechanisms of ERα and PR have been extensively studied in other contexts [41, 43], their function and mechanism in physiology and neoplastic disease of the human cervix remain underexplored. Studies using the validated HPV transgenic mouse model have provided new insights: estrogen and stromal ERα promote cervical cancer via a paracrine mechanism, and progesterone and PR suppress cervical cancer. Even though the mouse model results are encouraging and compelling, the ultimate question is whether targeting ERα and PR signaling pathways improves cervical cancer patients’ survival. In this regard, determining the clinical responsiveness of recurrent and metastatic cervical cancer to these approaches should be of utmost priority. The development of a novel preclinical mouse model of metastatic cervical cancer is also urgently needed. For a clinical trial, patient selection should be driven by biomarkers (e.g., PR and stromal ERα). SERMs and progestins should be chosen carefully because they result in distinct phenotypes in different tissues and because their function in the human cervix is poorly characterized [27, 76].

Summary

  • Cervical cancer is still the number one cause of cancer death in women in underdeveloped and developing countries, and a novel therapeutic modality is urgently needed.

  • HPV transgenic mouse models are powerful tools to study the pathogenesis of cervical cancer.

  • In mouse models, ERα expressed in cancer stroma but not in cancer cells is crucial for cervical cancer growth.

  • Pgr is a haploinsufficient tumor suppressor gene in mouse models, and progestins have therapeutic and preventive effects on cervical cancer.

  • The mechanism of ERα and PR in the human cervix, particularly in the transformation zone, needs to be determined.

Acknowledgment

The work of SHC is supported by the National Institutes of Health (R01 CA188646) and the Cancer Prevention and Research Institute of Texas (RP180275).

Footnotes

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

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