Skip to main content
SpringerLink
Log in

Gynecologic Cancers

  • Chapter
  • First Online:
Translation and Its Regulation in Cancer Biology and Medicine

Abstract

Despite major advances in understanding, prevention and treatment of gynecologic cancers, they still remain a common cause of morbidity and mortality for women. New insights into the molecular aspects of etiology and pathogenesis have identified involvement of multiple oncogenic signaling pathways. Translational regulation is an important mechanism of tumorigenesis. In this chapter, the important roles of translation factors, such as proto-oncogene eIF4E and its inhibitory binding proteins, 4E-BPs, as well as tumor suppressor PDCD4 are discussed in the context of gynecologic cancers. An outline of targeted therapies addressing aberrant function of these factors and their regulation is also presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Bae-Jump VL, Zhou C, Boggess JF, Whang YE, Barroilhet L, Gehrig PA (2010) Rapamycin inhibits cell proliferation in type I and type II endometrial carcinomas: a search for biomarkers of sensitivity to treatment. Gynecol Oncol 119:579–585

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Banerjee S, Kaye S (2011) The role of targeted therapy in ovarian cancer. Eur J Cancer 47(Suppl 3):S116–S130

    Article  PubMed  CAS  Google Scholar 

  • Banerjee S, Kaye SB (2012) Gynecological cancer: first-line bevacizumab for ovarian cancer-new standard of care? Nat Rev Clin Oncol 9:194–196

    Article  PubMed  CAS  Google Scholar 

  • Banerjee S, Kaye SB (2013) New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res 19:961–968

    Article  PubMed  CAS  Google Scholar 

  • Benavente S, Verges R, Hermosilla E, Fumanal V, Casanova N, Garcia A, Ramon YCS, Giralt J (2009) Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy. Int J Radiat Oncol Biol Phys 75:1316–1322

    Article  PubMed  CAS  Google Scholar 

  • Benelli D, Cialfi S, Pinzaglia M, Talora C, Londei P (2012) The translation factor eIF6 is a Notch-dependent regulator of cell migration and invasion. PloS ONE 7:e32047

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Carden CP, Stewart A, Thavasu P, Kipps E, Pope L, Crespo M, Miranda S, Attard G, Garrett MD, Clarke PA et al (2012) The association of PI3 kinase signaling and chemoresistance in advanced ovarian cancer. Mol Cancer Ther 11:1609–1617

    Article  PubMed  CAS  Google Scholar 

  • Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J, Ramon y Cajal S (2006) Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 107:1801–1811

    Article  PubMed  CAS  Google Scholar 

  • CDC/NCI (2013) U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999-2010 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. http://www.cdc.gov/uscs. Accessed Feb 2014

  • Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, Lu Y, Stemke-Hale K, Dyer MD, Zhang F et al (2011) High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discovery 1:170–185

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Choi CH, Lee JS, Kim SR, Lee YY, Kim CJ, Lee JW, Kim TJ, Lee JH, Kim BG, Bae D (2011) Direct inhibition of eIF4E reduced cell growth in endometrial adenocarcinoma. J Cancer Res Clin Oncol 137:463–469

    Article  PubMed  CAS  Google Scholar 

  • Colombo N, McMeekin DS, Schwartz PE, Sessa C, Gehrig PA, Holloway R, Braly P, Matei D, Morosky A, Dodion PF et al (2013) Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 108:1021–1026

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Darb-Esfahani S, Faggad A, Noske A, Weichert W, Buckendahl AC, Muller B, Budczies J, Roske A, Dietel M, Denkert C (2009) Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro. J Cancer Res Clin Oncol 135:933–941

    Article  PubMed  CAS  Google Scholar 

  • De Marco C, Rinaldo N, Bruni P, Malzoni C, Zullo F, Fabiani F, Losito S, Scrima M, Marino FZ, Franco R et al (2013) Multiple genetic alterations within the PI3K pathway are responsible for AKT activation in patients with ovarian carcinoma. PloS ONE 8:e55362

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Deftereos G, Corrie SR, Feng Q, Morihara J, Stern J, Hawes SE, Kiviat NB (2011) Expression of mir-21 and mir-143 in cervical specimens ranging from histologically normal through to invasive cervical cancer. PloS ONE 6:e28423

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Dellas A, Torhorst J, Bachmann F, Banziger R, Schultheiss E, Burger MM (1998) Expression of p150 in cervical neoplasia and its potential value in predicting survival. Cancer 83:1376–1383

    Article  PubMed  CAS  Google Scholar 

  • Faried LS, Faried A, Kanuma T, Aoki H, Sano T, Nakazato T, Tamura T, Kuwano H, Minegishi T (2008) Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: a potential biomarker and molecular target therapy. Mol Carcinog 47:446–457

    Article  PubMed  CAS  Google Scholar 

  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2008) GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 (Internet). Lyon, France: International Agency for Research on Cancer; 2010. http://globocan.iarc.fr.. Accessed 13 Nov 2013

  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

    Article  PubMed  CAS  Google Scholar 

  • Farley J, Brady WE, Vathipadiekal V, Lankes HA, Coleman R, Morgan MA, Mannel R, Yamada SD, Mutch D, Rodgers WH et al (2013) Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 14:134–140

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Flavin RJ, Smyth PC, Finn SP, Laios A, O’Toole SA, Barrett C, Ring M, Denning KM, Li J, Aherne ST et al (2008) Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients. Mod Pathol 21:676–684

    Article  PubMed  CAS  Google Scholar 

  • Givant-Horwitz V, Davidson B, Lazarovici P, Schaefer E, Nesland JM, Trope CG, Reich R (2003) Mitogen-activated protein kinases (MAPK) as predictors of clinical outcome in serous ovarian carcinoma in effusions. Gynecol Oncol 91:160–172

    Article  PubMed  CAS  Google Scholar 

  • Glaysher S, Bolton LM, Johnson P, Atkey N, Dyson M, Torrance C, Cree IA (2013) Targeting EGFR and PI3K pathways in ovarian cancer. Br J Cancer 109:1786–1794

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM (2013) Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol 71:1315–1323

    Article  PubMed  CAS  Google Scholar 

  • Group F.I.S. (2007) Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356:1915–1927

    Article  Google Scholar 

  • Harasawa M, Yasuda M, Hirasawa T, Miyazawa M, Shida M, Muramatsu T, Douguchi K, Matsui N, Takekoshi S, Kajiwara H et al (2011) Analysis of mTOR inhibition-involved pathway in ovarian clear cell adenocarcinoma. Acta Histochem Cytochem 44:113–118

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ko SY, Guo H, Barengo N, Naora H (2009) Inhibition of ovarian cancer growth by a tumor-targeting peptide that binds eukaryotic translation initiation factor 4E. Clin Cancer Res 15:4336–4347

    Article  PubMed  CAS  Google Scholar 

  • Laudanski P, Kowalczuk O, Klasa-Mazurkiewicz D, Milczek T, Rysak-Luberowicz D, Garbowicz M, Baranowski W, Charkiewicz R, Szamatowicz J, Chyczewski L (2011) Selective gene expression profiling of mTOR-associated tumor suppressor and oncogenes in ovarian cancer. Folia Histochem Cytobiol 49:317–324

    Article  PubMed  Google Scholar 

  • Lee JW, Choi JJ, Lee KM, Choi CH, Kim TJ, Lee JH, Kim BG, Ahn G, Song SY, Bae D (2005) eIF-4E expression is associated with histopathologic grades in cervical neoplasia. Hum Pathol 36:1197–1203

    Article  PubMed  CAS  Google Scholar 

  • Li X, Xiao L, Yang Y, Shen H, Zeng H, Wang Z (2008) The expression of mammalian target of rapamycin in Ishikawa and HEC-1 A cells. J Huazhong Uni Sci Technolog Med Sci 28:340–342

    Article  Google Scholar 

  • Liu S, Fang Y, Shen H, Xu W, Li H (2013) Berberine sensitizes ovarian cancer cells to cisplatin through miR-21/PDCD4 axis. Biochim Biophys Acta 45:756–762

    CAS  Google Scholar 

  • Lomnytska MI, Becker S, Hellman K, Hellstrom AC, Souchelnytskyi S, Mints M, Hellman U, Andersson S, Auer G (2010) Diagnostic protein marker patterns in squamous cervical cancer. Proteomics 4:17–31

    PubMed  CAS  Google Scholar 

  • Lou Y, Cui Z, Wang F, Yang X, Qian J (2011) miR-21 down-regulation promotes apoptosis and inhibits invasion and migration abilities of OVCAR3 cells. Clin Invest Med 34:E281

    PubMed  CAS  Google Scholar 

  • Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, Schilder RJ, Ozols RF, Testa JR (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261–4270

    Article  PubMed  CAS  Google Scholar 

  • Matthews-Greer J, Caldito G, de Benedetti A, Herrera GA, Dominguez-Malagon H, Chanona-Vilchis J, Turbat-Herrera EA (2005) eIF4E as a marker for cervical neoplasia. Appl Immunohistochem Mol Morphol 13:367–370

    Article  PubMed  CAS  Google Scholar 

  • Mazzoletti M, Bortolin F, Brunelli L, Pastorelli R, Di Giandomenico S, Erba E, Ubezio P, Broggini M (2011) Combination of PI3K/mTOR inhibitors: antitumor activity and molecular correlates. Cancer Res 71:4573–4584

    Article  PubMed  CAS  Google Scholar 

  • Montero JC, Chen X, Ocana A, Pandiella A (2012) Predominance of mTORC1 over mTORC2 in the regulation of proliferation of ovarian cancer cells: therapeutic implications. Mol Cancer Ther 11:1342–1352

    Article  PubMed  CAS  Google Scholar 

  • Myers AP (2013) New strategies in endometrial cancer: targeting the PI3K/mTOR pathway-the devil is in the details. Clin Cancer Res 19:5264–5274

    Article  PubMed  CAS  Google Scholar 

  • No JH, Jeon YT, Park IA, Kim YB, Kim JW, Park NH, Kang SB, Han JY, Lim JM, Song Y (2011) Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer. Gynecol Oncol 121:8–12

    Article  PubMed  CAS  Google Scholar 

  • Noske A, Lindenberg JL, Darb-Esfahani S, Weichert W, Buckendahl AC, Roske A, Sehouli J, Dietel M, Denkert C (2008) Activation of mTOR in a subgroup of ovarian carcinomas: correlation with p-eIF-4E and prognosis. Oncol Rep 20:1409–1417

    PubMed  CAS  Google Scholar 

  • Oh KJ, Kalinina A, Park NH, Bagchi S (2006) Deregulation of eIF4E: 4E-BP1 in differentiated human papillomavirus-containing cells leads to high levels of expression of the E7 oncoprotein. J Virol 80:7079–7088

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, Gotlieb WH, Hoskins PJ, Ghatage P, Tonkin KS et al (2011) Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol 29:3278–3285

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Parsyan A, Shahbazian D, Martineau Y, Petroulakis E, Alain T, Larsson O, Mathonnet G, Tettweiler G, Hellen CU, Pestova TV et al (2009) The helicase protein DHX29 promotes translation initiation, cell proliferation, and tumorigenesis. Proc Natl Acad Sci U S A 106:22217–22222

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stähle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM, ICON7 Investigators (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484-2496. doi: 10.1056/NEJMoa1103799

    Google Scholar 

  • Rice LW, Stone RL, Xu M, Galgano M, Stoler MH, Everett EN, Jazaeri AA (2006) Biologic targets for therapeutic intervention in endometrioid endometrial adenocarcinoma and malignant mixed mullerian tumors. Am J Obstet Gynecol 194:1119–1126; discussion 1126 − 1118

    Article  PubMed  CAS  Google Scholar 

  • Rico C, Lague MN, Lefevre P, Tsoi M, Dodelet-Devillers A, Kumar V, Lapointe E, Paquet M, Nadeau ME, Boerboom D (2012) Pharmacological targeting of mammalian target of rapamycin inhibits ovarian granulosa cell tumor growth. Carcinogenesis 33:2283–2292

    Article  PubMed  CAS  Google Scholar 

  • Shafer A, Zhou C, Gehrig PA, Boggess JF, Bae-Jump VL (2010) Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Int J Cancer 126:1144–1154

    PubMed  CAS  PubMed Central  Google Scholar 

  • Shen Q, Stanton ML, Feng W, Rodriguez ME, Ramondetta L, Chen L, Brown RE, Duan X (2010) Morphoproteomic analysis reveals an overexpressed and constitutively activated phospholipase D1-mTORC2 pathway in endometrial carcinoma. Int J Clin Exp Pathol 4:13–21

    PubMed  PubMed Central  Google Scholar 

  • Sheppard KE, Cullinane C, Hannan KM, Wall M, Chan J, Barber F, Foo J, Cameron D, Neilsen A, Ng P et al (2013) Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur J Cancer 49:3936–3944

    Article  PubMed  CAS  Google Scholar 

  • Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, Walker C, Ramondetta LM, Burke TW, Gershenson DM et al (2010) A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116:5415–5419

    Article  PubMed  CAS  Google Scholar 

  • Slomovitz BM, Brown J, Johnston TA, Mura D, Levenback C, Wolf J, Adler KR, Lu KH, Coleman RL (2011) A phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. Paper presented at: J Clin Oncol vol 29, 2011 ASCO annual meeting abstracts. http://meetinglibrary.asco.org/content/80682-102

  • Suh DH, Kim JW, Kim K, Kim HJ, Lee KH (2013) Major clinical research advances in gynecologic cancer in 2012. J Gynecol Oncol 24:66–82

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Tinker AV, Ellard S, Welch S, Moens F, Allo G, Tsao MS, Squire J, Tu D, Eisenhauer EA, MacKay H (2013) Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol 130:269–274

    Article  PubMed  CAS  Google Scholar 

  • Torres A, Torres K, Paszkowski T, Radej S, Staskiewicz GJ, Ceccaroni M, Pesci A, Maciejewski R (2011) Highly increased maspin expression corresponds with up-regulation of miR-21 in endometrial cancer: a preliminary report. Int J Gynecol Cancer 21:8–14

    Article  PubMed  Google Scholar 

  • Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Wei Z, Gao F, Zhang X, Zhou C, Zhu F, Wang Q, Gao Q, Ma C, Sun W et al (2008) Expression and prognostic significance of PDCD4 in human epithelial ovarian carcinoma. Anticancer Res 28:2991–2996

    PubMed  CAS  Google Scholar 

  • Wang M1, Wang Y, Zang W, Wang H, Chu H, Li P, Li M, Zhang G, Zhao G (2014) Downregulation of microRNA-182 inhibits cell growth and invasion by targeting programmed cell death 4 in human lung adenocarcinoma cells. Tumour Biol 35(1):39 -46. doi: 10.1007/s13277-013-1004-8. Epub 2013 Jul 23

    Google Scholar 

  • Wang S, Pang T, Gao M, Kang H, Ding W, Sun X, Zhao Y, Zhu W, Tang X, Yao Y et al (2013a) HPV E6 induces eIF4E transcription to promote the proliferation and migration of cervical cancer. FEBS Lett 587:690–697

    Article  CAS  Google Scholar 

  • Wang YQ, Guo RD, Guo RM, Sheng W, Yin LR (2013b) MicroRNA-182 promotes cell growth, invasion, and chemoresistance by targeting programmed cell death 4 (PDCD4) in human ovarian carcinomas. J Cell Biochem 114:1464–1473

    Article  CAS  Google Scholar 

  • Wei NA, Liu SS, Leung TH, Tam KF, Liao XY, Cheung AN, Chan KK, Ngan HY (2009a) Loss of Programmed cell death 4 (Pdcd4) associates with the progression of ovarian cancer. Mol Cancer 8:70

    Article  CAS  Google Scholar 

  • Wei ZT, Zhang X, Wang XY, Gao F, Zhou CJ, Zhu FL, Wang Q, Gao Q, Ma CH, Sun WS et al (2009b) PDCD4 inhibits the malignant phenotype of ovarian cancer cells. Cancer Sci 100:1408–1413

    Article  CAS  Google Scholar 

  • Wei N, Liu SS, Chan KK, Ngan HY (2012) Tumour suppressive function and modulation of programmed cell death 4 (PDCD4) in ovarian cancer. PloS ONE 7:e30311

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Weiderpass E, Labreche F (2012) Malignant tumors of the female reproductive system. SafHealth Work 3:166–180

    CAS  Google Scholar 

  • Weigelt B, Banerjee S (2012) Molecular targets and targeted therapeutics in endometrial cancer. Curr Opin Oncol 24:554–563

    Article  PubMed  CAS  Google Scholar 

  • Yao Q, Xu H, Zhang QQ, Zhou H, Qu LH (2009) MicroRNA-21 promotes cell proliferation and down-regulates the expression of programmed cell death 4 (PDCD4) in HeLa cervical carcinoma cells. Biochem Biophys Res Commun 388:539–542

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Wang X, Song X, Liu C, Shi Y, Wang Y, Afonja O, Ma C, Chen YH, Zhang L (2010) Programmed cell death 4 enhances chemosensitivity of ovarian cancer cells by activating death receptor pathway in vitro and in vivo. Cancer Sci 101:2163–2170

    Article  PubMed  CAS  Google Scholar 

  • Zhou C, Gehrig PA, Whang YE, Boggess JF (2003) Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells. Mol Cancer Ther 2:789–795

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of General Surgery, Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada

    Armen Parsyan

  2. Gynaecology Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London, UK

    Susana Banerjee

Authors
  1. Armen Parsyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susana Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Armen Parsyan .

Editor information

Editors and Affiliations

  1. Surgery, McGill University, Montreal, Québec, Canada

    Armen Parsyan

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Parsyan, A., Banerjee, S. (2014). Gynecologic Cancers. In: Parsyan, A. (eds) Translation and Its Regulation in Cancer Biology and Medicine. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9078-9_32

Download citation

Publish with us

Policies and ethics

Search

Navigation