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Estrogen and ERα: Culprits in cervical cancer?

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Estrogen and its receptors are implicated in the promotion and prevention of various cancers. Although the uterine cervix is highly responsive to estrogen, the role of estrogen in cervical cancer, which is strongly associated with human papillomavirus (HPV) infections, is poorly understood. Recent studies in HPV transgenic mouse models provide evidence that estrogen and its nuclear receptor promote cervical cancer in combination with HPV oncogenes. Although epidemiological studies further support this hypothesis, there is little experimental data assessing the hormonal responsiveness of human cervical cancers. If these cancers are dependent on estrogen, then drugs targeting estrogen and its receptors could be effective in treating and/or preventing cervical cancer, the second leading cause of death by cancer among women worldwide.

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Estrogen and cancer

Estrogen, through its nuclear receptors ERα and ERβ, and membrane receptor GPR30, influences physiological processes in various tissues/systems including but not limited to the female reproductive tract, breast, colon, brain, bone, cardiovascular and immune systems (Figure 1a). Not surprisingly, estrogen is implicated in various human diseases including cancer (e.g. breast, endometrium and colon) wherein it can either promote or suppress tumor development [1]. The uterine cervix is a part of

Cervical cancer

Cervical cancer is the second most frequent cancer and the second leading cause of cancer death in women worldwide, with approximately 470,000 new cases and 233,000 deaths per year [2]. The high mortality rate is largely as a result of the lack of effective therapies for eliminating disease in women with high-grade cervical cancer and the lack of response to chemotherapy of inoperable disease. A major causal factor for cervical cancer is the high-risk human papillomaviruses (HPVs), which are

Estrogen synergizes with HPV oncogenes to cause cervical cancer in mice

The strongest evidence that estrogen contributes to cervical carcinogenesis comes from laboratory studies on HPV transgenic mice. In these mice, multiple or individual HPV oncogenes (i.e. E6 and E7) are placed under the transcriptional control of the human keratin 14 promoter, which directs their expression to stratified squamous epithelia including that of the skin, oral cavity, anus, vagina and cervix. Although these HPV transgenic mice can develop spontaneous tumors, primarily in the skin,

Role of the ERα in cervical carcinogenesis

Despite intrinsic caveats of most genetically modified mouse models including available HPV transgenic mice [15], HPV transgenic mice have provided a powerful experimental platform for dissecting the roles of viral and host genes in cervical cancer 16, 17, 18, 19, 20. Given the potency of estrogen in inducing cervical cancer in these mice, the roles of its nuclear receptor ERα (ERβ was undetectable in the mouse cervix, as is the case in the human cervix) was investigated [21]. In contrast to

Targeting ERα: a new mode of treating and/or preventing cervical cancer

With the knowledge that ERα is required for carcinogenic activities of estrogen in the cervix [21] and that estrogen contributes not only to the genesis but also to the maintenance of cervical neoplastic disease [14], the utility of ERα antagonistic drugs in treating or preventing cervical cancer was evaluated using this HPV transgenic mouse model. Two ERα antagonists were evaluated, raloxifene and fulvestrant [22]. These are Federal Drug Administration-approved drugs used in the

The interplay between estrogen and HPV

That there is such a strong synergy between estrogen and HPV oncogenes in the development of cervical cancers in mice solicits the question – What is responsible for the high degree of interaction? Both estrogen and HPV E7 can independently induce cervical epithelial hyperplasia [21]. In addition, estrogen and HPV oncoproteins regulate Eag1 potassium channel, of which inhibition leads to apoptosis of human cervical cancer cells [23]. Chronic exposure to estrogen induces overexpression of

Epidemiological data on the role of sex hormones in human cervical cancer

Although incidence for most epithelial cancers increases with age, estrogen-dependent cancers do not share this age pattern [39]. Instead, after menopause they either increase more slowly, or cease to increase, depending on the level of circulating and/or local estrogens. Breast cancer is the best-studied example of estrogen-dependent epithelial cancer 39, 40, and knowledge gained from such studies has led to the vast use of SERMs in breast cancer treatment [41], as well as the consideration of

SERMs and cervical cancer

Because the cervix is highly responsive to estrogen, it has long been suspected that estrogen can contribute to cervical cancer. Based on this, several clinical trials have been carried out with tamoxifen that provided inconclusive results 52, 53. Unfortunately, tamoxifen was a poor choice of SERM to use as it acts as an ER agonist rather than ER antagonist in human cervix and vagina [54]. Tamoxifen has also been evaluated for its effect on proliferation of human cervical cancer cell lines;

Concluding remarks

Several lines of evidence support a role for estrogen and ERα in human cervical cancer. First, long-term use of oral contraceptives and/or multiple pregnancies increases the risk of cervical cancer, and cervical cancer incidence plateaus after menopause. Second, estrogen and ERα are required for cervical carcinogenesis, and SERMs are effective in controlling cervical cancer in well-validated mouse models for HPV-associated cervical cancer. Third, cervical cancer is often positive for ERα,

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