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Are Selective Estrogen Receptor Modulators (SERMs) a Therapeutic Option for HPV-Associated Cervical Lesions and Cancers?

2013; Elsevier BV; Volume: 184; Issue: 2 Linguagem: Inglês

10.1016/j.ajpath.2013.11.005

1525-2191

Karl Münger,

Cytokine Signaling Pathways and Interactions

In this issue of The American Journal of Pathology, Spurgeon et al1Spurgeon M.E. Chung S.H. Lambert P.F. Recurrence of cervical cancer in mice following selective estrogen receptor modulator therapy.Am J Path. 2014; 184: 530-540Abstract Full Text Full Text PDF Scopus (32) Google Scholar report on their evaluation of selective estrogen receptor modulators (SERMs) as potential therapeutic agents for human papillomavirus (HPV)-associated cancer. They use a mouse model of HPV16 and estrogen-driven cervical cancer for their studies and focus on the oral SERM, raloxifene, which was approved by the Food and Drug Administration. Consistent with their previous publication2Chung S.H. Lambert P.F. Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists.Proc Natl Acad Sci U S A. 2009; 106: 19467-19472Google Scholar they report that raloxifene causes regression of cervical lesions and tumors. Their major new findings are that tumors reappear after raloxifene withdrawal; these tumors preferentially arise within the outer cervix and the vagina; they likely represent recurrence of incompletely eradicated tumors rather than emergence of new cancers and, most interestingly, even though recurring tumors can arise in the absence of exogenous estrogen, they remain raloxifene-sensitive.1Spurgeon M.E. Chung S.H. Lambert P.F. Recurrence of cervical cancer in mice following selective estrogen receptor modulator therapy.Am J Path. 2014; 184: 530-540Abstract Full Text Full Text PDF Scopus (32) Google ScholarHuman Papillomaviruses, Estrogen, and Cervical CancerApproximately 5% of all human cancers are caused by HPV infections. The so-called high-risk HPVs, most prominently HPV16 and HPV18, are the etiological agents of almost all cases of cervical carcinoma, a leading cause of cancer death in women worldwide. Several other anogenital tract cancers, including anal, vulvar, vaginal, and penile cancers, are frequently caused by HPVs.3Schiffman M. Castle P.E. Jeronimo J. Rodriguez A.C. Wacholder S. Human papillomavirus and cervical cancer.Lancet. 2007; 370: 890-907Google Scholar A fraction of head and neck carcinomas, particularly oropharyngeal carcinomas, are also caused by high-risk HPV infections.4Gillison M.L. Koch W.M. Capone R.B. Spafford M. Westra W.H. Wu L. Zahurak M.L. Daniel R.W. Viglione M. Symer D.E. Shah K.V. Sidransky D. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.J Natl Cancer Inst. 2000; 92: 709-720Google Scholar Despite the clinical approval of efficacious prophylactic vaccines, the limited availability of these vaccines in low-resource countries and their disappointingly limited utilization in many high-resource countries will, unfortunately, limit their impact on HPV-associated cancer rates for decades to come. Moreover, the prophylactic vaccines do not modify disease development in individuals that have already been infected, and cancers often arise years, if not decades, after the initial infection. Hence, basic research that may yield translatable insights to the development of efficacious therapies for high-risk HPV-associated lesions and cancers remains an important endeavor.The viral E6 and E7 proteins are regularly expressed in HPV-associated cancers and they are necessary for the induction and maintenance of the transformed state. HPV E6 and E7 are small, multifunctional proteins that lack intrinsic enzymatic and specific DNA-binding activities. They act by associating with and functionally reprogramming cellular regulatory protein complexes, thereby compromising critical cellular signal transduction pathways including those controlled by the p53 and retinoblastoma tumor suppressors, respectively. The high-risk HPV E6 and E7 proteins also facilitate malignant progression by subverting mechanisms that safeguard genomic stability; hence, it is not surprising that long-term persistent high-risk HPV infection is the most prominent risk factor for cervical cancer development.5McLaughlin-Drubin M.E. Meyers J. Munger K. Cancer associated human papillomaviruses.Curr Opin Virol. 2012; 2: 459-466Google Scholar Attempts to identify environmental or genetic risk factors that modify the incidence of malignant progression of high-risk HPV-associated lesions have yielded only limited insights. Many of the traditional strong drivers of cancer development, such as smoking, only modestly increase the risk for invasive cervical carcinoma development,6Vaccarella S. Herrero R. Snijders P.J. Dai M. Thomas J.O. Hieu N.T. Ferreccio C. Matos E. Posso H. de Sanjose S. Shin H.R. Sukvirach S. Lazcano-Ponce E. Munoz N. Meijer C.J. Franceschi S. IARC HPV Prevalence Surveys (IHPS) Study GroupSmoking and human papillomavirus infection: pooled analysis of the International Agency for Research on Cancer HPV Prevalence Surveys.I J Epidemiol. 2008; 37: 536-546Google Scholar and HPV-associated oral cancers often occur in younger patients who are less likely to have a long-term history of tobacco and/or alcohol abuse.4Gillison M.L. Koch W.M. Capone R.B. Spafford M. Westra W.H. Wu L. Zahurak M.L. Daniel R.W. Viglione M. Symer D.E. Shah K.V. Sidransky D. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.J Natl Cancer Inst. 2000; 92: 709-720Google Scholar Some of the nonviral risk factors for invasive cervical cancer development are multiparity and long-term contraceptive use7Chung S.H. Franceschi S. Lambert P.F. Estrogen and ERalpha: culprits in cervical cancer?.Trends Endocrinol Metab. 2010; 21: 504-511Google Scholar for which each has been correlated with elevated estrogen exposure.HPV Tumorigenesis: A Consequence of HPV Gene Expression in Conjunction With Cell-Type Specific Cocarcinogen Exposure?The authors performed their studies with a transgenic mouse model of cervical cancer in which the HPV16 E6 and E7 genes were expressed in basal epithelial cells from a human keratin K14 promoter. Cervical cancer development in this model is critically dependent on HPV oncogene expression and on chronic exposure to low doses of estrogen that mimic continuous estrus.8Arbeit J.M. Howley P.M. Hanahan D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice.Proc Natl Acad Sci U S A. 1996; 93: 2930-2935Google Scholar, 9Elson D.A. Riley R.R. Lacey A. Thordarson G. Talamantes F.J. Arbeit J.M. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis.Cancer Res. 2000; 60: 1267-1275Google Scholar The cocarcinogenic effect of estrogen is dependent on estrogen receptor α signaling in the tumor stroma, suggesting that paracrine mechanisms may be involved.10Chung S.H. Shin M.K. Korach K.S. Lambert P.F. Requirement for stromal estrogen receptor alpha in cervical neoplasia.Horm Cancer. 2013; 4: 50-59Google ScholarEven though the transgenic mice uniformly express HPV16 E6 and E7 in all basal epithelial cells, and tumor formation can be triggered at other anatomical locations by application of various cocarcinogens,11Stelzer M.K. Pitot H.C. Liem A. Schweizer J. Mahoney C. Lambert P.F. A mouse model for human anal cancer.Cancer Prev Res (Phila). 2010; 3: 1534-1541Google Scholar, 12Strati K. Pitot H.C. Lambert P.F. Identification of biomarkers that distinguish human papillomavirus (HPV)-positive versus HPV-negative head and neck cancers in a mouse model.Proc Natl Acad Sci U S A. 2006; 103: 14152-14157Google Scholar HPV16 E6/E7 transgenic mice treated with low doses of estrogen specifically develop cervical carcinoma.9Elson D.A. Riley R.R. Lacey A. Thordarson G. Talamantes F.J. Arbeit J.M. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis.Cancer Res. 2000; 60: 1267-1275Google Scholar Hence, the cervical cancers in this mouse model must arise from a specific cell type in which the functional interplay of low-level estrogen exposure and HPV E6/E7 expression triggers malignant transformation at a far greater rate than in any other cell type. Indeed, previous studies with this mouse model have revealed that the cancers arise from a population of reserve cells at the cervical squamocolumnar transformation zone, which can acquire squamous or columnar epithelial cell fates.9Elson D.A. Riley R.R. Lacey A. Thordarson G. Talamantes F.J. Arbeit J.M. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis.Cancer Res. 2000; 60: 1267-1275Google Scholar, 13Chung S.H. Wiedmeyer K. Shai A. Korach K.S. Lambert P.F. Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer.Cancer Res. 2008; 68: 9928-9934Google Scholar This is similar to high-risk HPV infected women in which cervical carcinomas are thought to result from HPV infection of a specific cell population at the cervical squamocolumnar transformation zone. These cells exhibit unique embryonic characteristics and a transcriptional profile that is distinct from that of the neighboring squamous and columnar epithelial cells.14Herfs M. Yamamoto Y. Laury A. Wang X. Nucci M.R. McLaughlin-Drubin M.E. Munger K. Feldman S. McKeon F.D. Xian W. Crum C.P. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer.Proc Natl Acad Sci U S A. 2012; 109: 10516-10521Google Scholar The cervical tumors in the mouse model are not only addicted to viral oncogene expression, but are also acutely dependent on continuous estrogen stimulation.15Jabbar S.F. Park S. Schweizer J. Berard-Bergery M. Pitot H.C. Lee D. Lambert P.F. Cervical cancers require the continuous expression of the human papillomavirus type 16 E7 oncoprotein even in the presence of the viral E6 oncoprotein.Cancer Res. 2012; 72: 4008-4016Google Scholar, 16Brake T. Lambert P.F. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model.Proc Natl Acad Sci U S A. 2005; 102: 2490-2495Google ScholarIt is uncertain whether human cervical carcinoma tumors are similarly strongly addicted to estrogen. On one hand, there does not appear to be a strong correlation between hormone replacement therapy and the incidence of HPV infection or cervical carcinoma, although a small study reported a higher incidence of HPV-associated adenocarcinomas, but not squamous cell carcinomas.17Smith E.M. Johnson S.R. Figuerres E.J. Mendoza M. Fedderson D. Haugen T.H. Turek L.P. The frequency of human papillomavirus detection in postmenopausal women on hormone replacement therapy.Gynecol Oncol. 1997; 65: 441-446Google Scholar, 18Lacey Jr., J.V. Brinton L.A. Barnes W.A. Gravitt P.E. Greenberg M.D. Hadjimichael O.C. McGowan L. Mortel R. Schwartz P.E. Kurman R.J. Hildesheim A. Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix.Gynecol Oncol. 2000; 77: 149-154Google Scholar, 19Gadducci A. Barsotti C. Cosio S. Domenici L. Riccardo Genazzani A. Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature.Gynecol Endocrinol. 2011; 27: 597-604Google Scholar On the other hand, the finding that estrogen exposure as a consequence of long-term oral contraceptive use or multiparity consistently scores as one of the few significant nonviral risk factors for progression of high-grade premalignant lesions to invasive cervical cancer7Chung S.H. Franceschi S. Lambert P.F. Estrogen and ERalpha: culprits in cervical cancer?.Trends Endocrinol Metab. 2010; 21: 504-511Google Scholar supports the concept that estrogen may also be a driver of malignant progression of HPV-infected human cervical epithelial cells.SERMs and Cervical Cancer DevelopmentAssuming that these findings are indeed translatable to clinical management of human cervical cancers, the current study provides some important new insights. As was previously pointed out, raloxifene and/or other SERMS with estrogen antagonistic activities in the female reproductive tract may be a novel, noninvasive treatment option for high-risk HPV-associated cervical lesions and possibly even cancers.2Chung S.H. Lambert P.F. Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists.Proc Natl Acad Sci U S A. 2009; 106: 19467-19472Google Scholar, 20Castle P.E. Do selective estrogen receptor modulators treat cervical precancer and cancer? Time to pool data from relevant trials.Int J Cancer. 2011; 128: 997-998Google Scholar However, SERMs may only temporarily halt the growth of HPV-associated cervical tumors. The authors speculate that tumors reappear in their model because "… residual cancer cells drive recurrence of cancer in mice on release from treatment with raloxifene."1Spurgeon M.E. Chung S.H. Lambert P.F. Recurrence of cervical cancer in mice following selective estrogen receptor modulator therapy.Am J Path. 2014; 184: 530-540Abstract Full Text Full Text PDF Scopus (32) Google Scholar This is a likely possibility, given that mice that were not previously exposed to estrogen and therefore did not bear tumors before raloxifene treatment showed less severe lesions on estrogen exposure than mice that were exposed to estrogen and had tumors before raloxifene treatment. Their model is also supported by the finding that the incidence of recurrence was decreased after longer-term SERM treatment. Maybe the most surprising finding of this study, however, is that the recurring tumors do not develop estrogen receptor α independence and remain sensitive to repeated SERM treatment.If translatable in humans, this would definitely be good news. Oral SERMs, such as raloxifene, have been widely prescribed for postmenopausal women not only for reducing the risk for developing invasive breast cancer (anti-estrogenic action), but also for the prevention of osteoporosis (pro-estrogenic action). However, long-term use of SERMs is not without risks, and there has been an increase in reported venous thromboembolisms in individuals with cardiovascular heart disease, even though no concomitant increase in coronary events was observed. There were also a significantly higher number of stroke fatalities, without affecting the overall incidence of strokes.21Barrett-Connor E. Mosca L. Collins P. Geiger M.J. Grady D. Kornitzer M. McNabb M.A. Wenger N.K. Raloxifene Use for The Heart Trial I: Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women.N Engl J Med. 2006; 355: 125-137Google Scholar Raloxifene would not be used in women who are pregnant or may become pregnant and, thus, it is unlikely that the current SERMs would be widely used for chemoprevention of HPV-associated cervical lesions and cancer in a generally younger, pre-menopausal population. However, novel SERMs that potentially provide better therapeutic responses with better safety profiles are being developed.22Reimers L. Crew K.D. Tamoxifen vs raloxifene vs exemestane for chemoprevention.Curr Breast Cancer Rep. 2012; 4: 207-215Google Scholar, 23Gara R.K. Sundram V. Chauhan S.C. Jaggi M. Anti-cancer potential of a novel SERM ormeloxifene.Curr Med Chem. 2013; 20: 4177-4184Google ScholarFuture DirectionsA number of interesting questions remain. What is the mechanism of the observed antineoplastic activity of raloxifene and related SERMs in this model? Does estrogen starvation cause tumor cell death, and if so, is there selective cell death of HPV-infected cells? Otherwise, does raloxifene trigger cell cycle withdrawal and/or terminal differentiation and the transformed cells are sloughed off? Given that metastatic disease develops very frequently and is responsible for the majority of cancer deaths, it will be important to determine whether cervical cancer metastases remain susceptible to SERMs. It will also be important to investigate whether raloxifene can be used in conjunction with other chemotherapy agents and/or whether it should be considered as an adjuvant therapy after surgical ablation of premalignant lesions or tumors.Although SERMs may also be useful to inhibit HPV-associated vulvar and vaginal carcinomas, it is unlikely that these drugs will provide a therapeutic benefit for HPV-associated anal, oral, and penile cancers, which are unlikely to be estrogen addicted. The general concept of starving an infected cell of a factor that is critical for cell maintenance and/or proliferation, however, may also be applicable to HPV-associated anal and oral cancers. It will be important to determine whether there are populations of anal and/or oral epithelial cells that are uniquely vulnerable to malignant transformation in response to HPV gene expression in conjunction with exposure to specific cocarcinogens. Not only is the incidence of high-risk HPV associated oral and anal cancers on the rise, but there are also no widely used procedures for early detection of precancerous lesions, and patients often present with late stage disease. The transgenic mouse model may play a critical role in identifying vulnerable cell populations at these anatomical locations because the tumors that arise in these transgenic mice express some of the same biomarkers as the human cancers.24Brake T. Connor J.P. Petereit D.G. Lambert P.F. Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer.Cancer Res. 2003; 63: 8173-8180Google Scholar Population-based studies may provide clues to the cocarcinogens that cooperate with viral gene expression and the transgenic mouse model may provide an excellent platform to experimentally test candidates.The molecular characterization of the cell types that are particularly vulnerable to malignant transformation upon HPV infection and cocarcinogen exposure may also allow for a more accurate identification of lesions that are at a particularly high risk for rapid malignant progression and require immediate clinical care. Although HPV testing, which currently complements and may eventually replace standard cytological tests for early detection of cervical lesions and cancer may be useful, there remains an unmet need for discovery of biomarkers that accurately predict the potential for malignant progression of a particular lesion. The cell population that has been implicated in the pathogenesis of cervical cancer expresses a unique set of genes, and it will be interesting to see whether a gene expression signature typical for these cells in conjunction with HPV typing and/or traditional cytological and histopathological procedures may be useful for this type of stratification.14Herfs M. Yamamoto Y. Laury A. Wang X. Nucci M.R. McLaughlin-Drubin M.E. Munger K. Feldman S. McKeon F.D. Xian W. Crum C.P. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer.Proc Natl Acad Sci U S A. 2012; 109: 10516-10521Google Scholar In this issue of The American Journal of Pathology, Spurgeon et al1Spurgeon M.E. Chung S.H. Lambert P.F. Recurrence of cervical cancer in mice following selective estrogen receptor modulator therapy.Am J Path. 2014; 184: 530-540Abstract Full Text Full Text PDF Scopus (32) Google Scholar report on their evaluation of selective estrogen receptor modulators (SERMs) as potential therapeutic agents for human papillomavirus (HPV)-associated cancer. They use a mouse model of HPV16 and estrogen-driven cervical cancer for their studies and focus on the oral SERM, raloxifene, which was approved by the Food and Drug Administration. Consistent with their previous publication2Chung S.H. Lambert P.F. Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists.Proc Natl Acad Sci U S A. 2009; 106: 19467-19472Google Scholar they report that raloxifene causes regression of cervical lesions and tumors. Their major new findings are that tumors reappear after raloxifene withdrawal; these tumors preferentially arise within the outer cervix and the vagina; they likely represent recurrence of incompletely eradicated tumors rather than emergence of new cancers and, most interestingly, even though recurring tumors can arise in the absence of exogenous estrogen, they remain raloxifene-sensitive.1Spurgeon M.E. Chung S.H. Lambert P.F. Recurrence of cervical cancer in mice following selective estrogen receptor modulator therapy.Am J Path. 2014; 184: 530-540Abstract Full Text Full Text PDF Scopus (32) Google Scholar Human Papillomaviruses, Estrogen, and Cervical CancerApproximately 5% of all human cancers are caused by HPV infections. The so-called high-risk HPVs, most prominently HPV16 and HPV18, are the etiological agents of almost all cases of cervical carcinoma, a leading cause of cancer death in women worldwide. Several other anogenital tract cancers, including anal, vulvar, vaginal, and penile cancers, are frequently caused by HPVs.3Schiffman M. Castle P.E. Jeronimo J. Rodriguez A.C. Wacholder S. Human papillomavirus and cervical cancer.Lancet. 2007; 370: 890-907Google Scholar A fraction of head and neck carcinomas, particularly oropharyngeal carcinomas, are also caused by high-risk HPV infections.4Gillison M.L. Koch W.M. Capone R.B. Spafford M. Westra W.H. Wu L. Zahurak M.L. Daniel R.W. Viglione M. Symer D.E. Shah K.V. Sidransky D. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.J Natl Cancer Inst. 2000; 92: 709-720Google Scholar Despite the clinical approval of efficacious prophylactic vaccines, the limited availability of these vaccines in low-resource countries and their disappointingly limited utilization in many high-resource countries will, unfortunately, limit their impact on HPV-associated cancer rates for decades to come. Moreover, the prophylactic vaccines do not modify disease development in individuals that have already been infected, and cancers often arise years, if not decades, after the initial infection. Hence, basic research that may yield translatable insights to the development of efficacious therapies for high-risk HPV-associated lesions and cancers remains an important endeavor.The viral E6 and E7 proteins are regularly expressed in HPV-associated cancers and they are necessary for the induction and maintenance of the transformed state. HPV E6 and E7 are small, multifunctional proteins that lack intrinsic enzymatic and specific DNA-binding activities. They act by associating with and functionally reprogramming cellular regulatory protein complexes, thereby compromising critical cellular signal transduction pathways including those controlled by the p53 and retinoblastoma tumor suppressors, respectively. The high-risk HPV E6 and E7 proteins also facilitate malignant progression by subverting mechanisms that safeguard genomic stability; hence, it is not surprising that long-term persistent high-risk HPV infection is the most prominent risk factor for cervical cancer development.5McLaughlin-Drubin M.E. Meyers J. Munger K. Cancer associated human papillomaviruses.Curr Opin Virol. 2012; 2: 459-466Google Scholar Attempts to identify environmental or genetic risk factors that modify the incidence of malignant progression of high-risk HPV-associated lesions have yielded only limited insights. Many of the traditional strong drivers of cancer development, such as smoking, only modestly increase the risk for invasive cervical carcinoma development,6Vaccarella S. Herrero R. Snijders P.J. Dai M. Thomas J.O. Hieu N.T. Ferreccio C. Matos E. Posso H. de Sanjose S. Shin H.R. Sukvirach S. Lazcano-Ponce E. Munoz N. Meijer C.J. Franceschi S. IARC HPV Prevalence Surveys (IHPS) Study GroupSmoking and human papillomavirus infection: pooled analysis of the International Agency for Research on Cancer HPV Prevalence Surveys.I J Epidemiol. 2008; 37: 536-546Google Scholar and HPV-associated oral cancers often occur in younger patients who are less likely to have a long-term history of tobacco and/or alcohol abuse.4Gillison M.L. Koch W.M. Capone R.B. Spafford M. Westra W.H. Wu L. Zahurak M.L. Daniel R.W. Viglione M. Symer D.E. Shah K.V. Sidransky D. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.J Natl Cancer Inst. 2000; 92: 709-720Google Scholar Some of the nonviral risk factors for invasive cervical cancer development are multiparity and long-term contraceptive use7Chung S.H. Franceschi S. Lambert P.F. Estrogen and ERalpha: culprits in cervical cancer?.Trends Endocrinol Metab. 2010; 21: 504-511Google Scholar for which each has been correlated with elevated estrogen exposure. Approximately 5% of all human cancers are caused by HPV infections. The so-called high-risk HPVs, most prominently HPV16 and HPV18, are the etiological agents of almost all cases of cervical carcinoma, a leading cause of cancer death in women worldwide. Several other anogenital tract cancers, including anal, vulvar, vaginal, and penile cancers, are frequently caused by HPVs.3Schiffman M. Castle P.E. Jeronimo J. Rodriguez A.C. Wacholder S. Human papillomavirus and cervical cancer.Lancet. 2007; 370: 890-907Google Scholar A fraction of head and neck carcinomas, particularly oropharyngeal carcinomas, are also caused by high-risk HPV infections.4Gillison M.L. Koch W.M. Capone R.B. Spafford M. Westra W.H. Wu L. Zahurak M.L. Daniel R.W. Viglione M. Symer D.E. Shah K.V. Sidransky D. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.J Natl Cancer Inst. 2000; 92: 709-720Google Scholar Despite the clinical approval of efficacious prophylactic vaccines, the limited availability of these vaccines in low-resource countries and their disappointingly limited utilization in many high-resource countries will, unfortunately, limit their impact on HPV-associated cancer rates for decades to come. Moreover, the prophylactic vaccines do not modify disease development in individuals that have already been infected, and cancers often arise years, if not decades, after the initial infection. Hence, basic research that may yield translatable insights to the development of efficacious therapies for high-risk HPV-associated lesions and cancers remains an important endeavor. The viral E6 and E7 proteins are regularly expressed in HPV-associated cancers and they are necessary for the induction and maintenance of the transformed state. HPV E6 and E7 are small, multifunctional proteins that lack intrinsic enzymatic and specific DNA-binding activities. They act by associating with and functionally reprogramming cellular regulatory protein complexes, thereby compromising critical cellular signal transduction pathways including those controlled by the p53 and retinoblastoma tumor suppressors, respectively. The high-risk HPV E6 and E7 proteins also facilitate malignant progression by subverting mechanisms that safeguard genomic stability; hence, it is not surprising that long-term persistent high-risk HPV infection is the most prominent risk factor for cervical cancer development.5McLaughlin-Drubin M.E. Meyers J. Munger K. Cancer associated human papillomaviruses.Curr Opin Virol. 2012; 2: 459-466Google Scholar Attempts to identify environmental or genetic risk factors that modify the incidence of malignant progression of high-risk HPV-associated lesions have yielded only limited insights. Many of the traditional strong drivers of cancer development, such as smoking, only modestly increase the risk for invasive cervical carcinoma development,6Vaccarella S. Herrero R. Snijders P.J. Dai M. Thomas J.O. Hieu N.T. Ferreccio C. Matos E. Posso H. de Sanjose S. Shin H.R. Sukvirach S. Lazcano-Ponce E. Munoz N. Meijer C.J. Franceschi S. IARC HPV Prevalence Surveys (IHPS) Study GroupSmoking and human papillomavirus infection: pooled analysis of the International Agency for Research on Cancer HPV Prevalence Surveys.I J Epidemiol. 2008; 37: 536-546Google Scholar and HPV-associated oral cancers often occur in younger patients who are less likely to have a long-term history of tobacco and/or alcohol abuse.4Gillison M.L. Koch W.M. Capone R.B. Spafford M. Westra W.H. Wu L. Zahurak M.L. Daniel R.W. Viglione M. Symer D.E. Shah K.V. Sidransky D. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.J Natl Cancer Inst. 2000; 92: 709-720Google Scholar Some of the nonviral risk factors for invasive cervical cancer development are multiparity and long-term contraceptive use7Chung S.H. Franceschi S. Lambert P.F. Estrogen and ERalpha: culprits in cervical cancer?.Trends Endocrinol Metab. 2010; 21: 504-511Google Scholar for which each has been correlated with elevated estrogen exposure. HPV Tumorigenesis: A Consequence of HPV Gene Expression in Conjunction With Cell-Type Specific Cocarcinogen Exposure?The authors performed their studies with a transgenic mouse model of cervical cancer in which the HPV16 E6 and E7 genes were expressed in basal epithelial cells from a human keratin K14 promoter. Cervical cancer development in this model is critically dependent on HPV oncogene expression and on chronic exposure to low doses of estrogen that mimic continuous estrus.8Arbeit J.M. Howley P.M. Hanahan D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice.Proc Natl Acad Sci U S A. 1996; 93: 2930-2935Google Scholar, 9Elson D.A. Riley R.R. Lacey A. Thordarson G. Talamantes F.J. Arbeit J.M. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis.Cancer Res. 2000; 60: 1267-1275Google Scholar The cocarcinogenic effect of estrogen is dependent on estrogen receptor α signaling in the tumor stroma, suggesting that paracrine mechanisms may be involved.10Chung S.H. Shin