Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC34110.15690/vramn.v67i2.118ONCOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ОНКОЛОГИИESTROGEN RECEPTORS Β — NEW TARGET IN CELLULAR LUNG CANCER TREATMENTЭСТРОГЕНОВЫЕ РЕЦЕПТОРЫ Β — НОВАЯ МИШЕНЬ В ТЕРАПИИ НЕМЕЛКОКЛЕТОЧНОГО РАКА ЛЕГКОГОDavydovM. I.ДавыдовМ. И.
Russian Federation

доктор медицинских наук, академик РАН и РАМН, профессор, директор Российского онкологического научного центра имени. Н.Н. Блохина РАМН Адрес: 115478, Москва, Каширское шоссе, д. 24 Тел./факс: (495) 932-85-68

bogush@orc.ruBogushT. A.БогушТ. А.
Russian Federation

доктор биологических наук, профессор, заслуженный деятель науки РФ, заведующая лабораторией медицинской химии Российского онкологического научного центра имени Н.Н. Блохина РАМН

bogush@orc.ruPolotskiiB. E.ПолоцкийБ. Е.
Russian Federation

доктор медицинских наук, профессор, ведущий научный сотрудник Российского онколо- гического научного центра имени Н.Н. Блохина РАМН

bogush@orc.ruTyulyandinS. A.ТюляндинС. А.
Russian Federation

доктор медицинских наук, профессор, руководитель отделения клинической фармако- логии и химиотерапии Российского онкологического научного центра имени Н.Н. Блохина РАМН

bogush@orc.ruFSBI «Blokhin Russian oncological scientific centre» RAMS, MoscowФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» РАМН, Москва22022012672Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук162207082015Copyright ©; 2012, "Paediatrician" Publishers LLCCopyright ©; 2012, Издательство "Педиатръ"2012"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/341

Literature review upon various types of estrogen receptors expression (type ? and ?) in the cells of cellular lung cancer, their participation in estrogen and antiestrogen effects implementation, influence of estrogens and antiestrogens on occurrence and progression of malignant lung tumors in animals and humans. Were analyzed reasons of data ambiguity on type ? estrogen receptors (ER?) expression frequency. The results of authors own research in quantitative assessment of ER? expression in tumor tissue of patients with cellular lung cancer (79 male and 22 female patients are presented in this article. An increase in expression rate and incidence of tumors with high ER? level has been shown in patients with lung adenocarcinoma regardless of smoking status or gender. A new strategy of antiestrogen use, especially tamoxifen, has been formulated for cellular lung cancer treatment. Authors believe in a positive effect of adjuvant treatment with tamoxifen in patients with ER?-positive cellular lung cancer used independently or during and after the chemotherapy, by analogy with breast cancer patients.

Обзор данных литературы об экспрессии разных типов эстрогеновых рецепторов (ЭРα и ЭРβ) в клетках немелкоклеточного рака легкого,их участии в реализации эффектов эстрогенов и антиэстрогенов, влиянии эстрогенов и антиэстрогенов на возникновение и прогрессию злокачественных опухолей легких у животных и человека. Проанализированы причины неоднозначности данных литературы о частоте экспрессии ЭРβ в ткани немелкоклеточного рака легкого. Представлены результаты собственных исследований авторов по количественной оценке экспрессии ЭРβ в опухолевой ткани пациентов с немелкоклеточным раком легкого (79 мужчин и 22 женщины). Показано повышение уровня экспрессии и частоты встречаемости опухолей с высоким уровнем ЭРβ в группе больных с аденокарциномой легкого независимо от статуса курения и пола пациентов. Сформулирована стратегия применения антиэстрогенов, в частности тамоксифена, при лечении немелкоклеточного рака легкого. Авторы полагают, что есть все основания рассчитывать на сходный с раком молочной железы положительный эффект тамоксифена при его адъювантном применении у больных с ЭРβ-положительными опухолями в качестве самостоятельного средства, а также в ходе и после завершения химиотерапии.

estrogen receptors α and βcellular lung cancerantiestrogenstamoxifenadjuvant treatmentэстрогеновые рецепторы α и βнемелкоклеточный рак легкогоантиэстрогенытамоксифенадъювантная терапия1. Brownson R.C., Chang, J.C., Davis J.R. Gender and histologic type variations in smoking-related risk of lung cancer. Epidemiology. 1992; 3 (1): 61–64.2. Radzikowska E., Glaz P., Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20561 cases. Ann. Oncol. 2002; 13 (7): 1087–1093.3. Siegfried J.M. Women and lung cancer: does oestrogen play a role? Lancet Oncol. 2001; 2 (8): 506–513.4. Bogush T.A., Dudko E.A., Beme A.A. et al. Antibiotiki i khimioterapiya = Antibiotics and chemotherapy. 2009; 54 (7-8): 41-49.5. Mollerup S., Jorgensen K., Berge G., Haugen A. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung. Cancer. 2002; 37 (2): 153–159.6. Hershberger P.A., Vasquez A.C., Kanterewicz B. et al. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Res. 2005; 65 (4): 1598–1605.7. Zhang G., Liu X., Farkas A.M. et al. Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells. Mol. Endocrinol. 2009; 23 (2): 146–156.8. Jarzynka M.J., Guo P., Bar-Joseph I. et al. Estradiol and nicotine exposure enhances A549 bronchioloalveolar carcinoma xenograft growth in mice through the stimulation of angiogenesis. Int. J. Oncol. 2006; 28 (2): 337–344.9. Stabile L.P., Gaither Davis A.L., Gubish C.T. et al. Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res. 2002; 62 (7): 2141–2150.10. Pietras R.J., Mаrquez D.C., Chen H.W. et al. Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Steroids. 2005; 70 (5–7): 372–381.11. Stabile L.P., Lyker J.S., Gubish C.T. et al. Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res. 2005; 65 (4): 1459–1470.12. Mаrquez-Garbаn D.C., Chen H.W., Fishbein M.C. et al. Estrogen receptor signaling pathways in human non-small cell lung cancer. Steroids. 2007; 72 (2): 135–143.13. Omoto Y., Kobayashi Y., Nishida K. et al. Expression, function, and clinical implications of the estrogen receptor beta in human lung cancers. Biochem. Biophys. Res. Commun. 2001; 285 (2): 340–347.14. Dougherty S.M., Mazhawidza W., Bohn A.R. et al. Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr. Relat. Cancer. 2006; 13 (1): 113–134.15. Mаrquez-Garbаn D.C., Chen H.W., Goodglick L. et al. Targeting aromatase and estrogen signaling in human non-small cell lung cancer. Ann. N. Y. Acad. Sci. 2009; 1155: 194–205.16. Shen H., Yuan Y., Sun J. et al. Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects. Biomed. Pharmacother. 2010; 64 (2): 88–92.17. Ciana P., Di Luccio G., Belcredito S. et al. Engineering of a mouse for the in vivo profiling of estrogen receptor activity. Mol. Endocrinol. 2001; 15 (7): 1104–1113.18. Hammoud Z., Tan B., Badve S., Bigsby R.M. Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma. Endocr. Relat. Cancer. 2008; 15 (2): 475–483.19. Taioli E., Wynder E.L. Re: Endocrine factors and adenocarcinoma of the lung in women. J. Natl. Cancer Inst.1994; 86 (11): 869–870.20. Ganti A.K., Sahmoun A.E., Panwalkar A.W. et al. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J. Clin. Oncol. 2006; 24 (1): 59–63.21. Rapiti E., Verkooijen H.M., Fioretta G. et al. Reduced lung cancer mortality risk among breast cancer patients treated with anti-estrogens. Cancer Res. 2009; 69 (Suppl. 24): 493.22. Traynor A.M., Schiller J.H., Stabile L.P. et al. Pilot study of gefitinib and fulvestrant in the treatment of post-menopausal women with advanced non-small cell lung cancer. Lung. Cancer. 2009; 64 (1): 51–59.23. Skov B.G., Fischer B.M., Pappot H. Oestrogen receptor beta over expression in males with non-small cell lung cancer is associated with better survival. Lung. Cancer. 2008; 59 (1): 88–94.24. Schwartz A.G., Prysak G.M., Murphy V. et al. Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex. Clin. Cancer Res. 2005; 11 (20): 7280–7287.25. Wu C.T., Chang Y.L., Shih J.Y., Lee Y.C. The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J. Thorac. Cardiovasc. Surg. 2005; 130 (4): 979–986.26. Kawai H., Ishii A., Washiya K. et al. Estrogen receptor alpha and beta are prognostic factors in non-small cell lung cancer. Clin. Cancer Res. 2005; 11(14): 5084–5089.27. Fasco M.J., Hurteau G.J., Spivack S.D. Gender-dependent expression of alpha and beta estrogen receptors in human nontumor and tumor lung tissue. Mol. Cell. Endocrinol. 2002; 188 (1–2): 125–140.28. Dabbs D.J., Landreneau R.J., Liu Y. et al. Detection of estrogen receptor by immunohistochemistry in pulmonary adenocarcinoma. Ann. Thorac. Surg. 2002; 73 (2): 403–406.29. Gomez-Fernandez C., Mejias A., Walker G., Nadji M. Immunohistochemical expression of estrogen receptor in adenocarcinomas of the lung: the antibody factor. Appl. Immunohistochem. Mol. Morphol. 2010; 18 (2): 137–141.30. Radzikowska E., Langfort R., Giedronowicz D. Estrogen and progesterone receptors in non small cell lung cancer patients. Ann. Thorac. Cardiovasc. Surg. 2002; 8 (2): 69–73.31. Lau S.K., Chu P.G., Weiss L.M. Immunohistochemical expression of estrogen receptor in pulmonary adenocarcinoma. Appl. Immunohistochem. Mol. Morphol. 2006; 14 (1): 83–87.32. Di Nunno L., Larsson L.G., Rinehart J.J., Beissner R.S. Estrogen and progesterone receptors in non-small cell lung cancer in 248 consecutive patients who underwent surgical resection. Arch. Pathol. Lab. Med. 2000; 124 (10): 1467–1470.33. Wu C.T., Chang Y.L., Lee Y.C. Expression of the estrogen receptor beta in 37 surgically treated pulmonary sclerosing hemangiomas in comparison with non-small cell lung carcinomas. Hum. Pathol. 2005; 36 (10): 1108–1112.34. Sica G., Wagner P.L., Altorki N. et al. Immunohistochemical expression of estrogen and progesterone receptors in primary pulmonary neuroendocrine tumors. Arch. Pathol. Lab. Med. 2008; 132 (12): 1889–1895.35. Ishibashi H., Suzuki T., Suzuki S. et al. Progesterone receptor in non-small cell lung cancer: a potent prognostic factor and possible target for endocrine therapy. Cancer Res. 2005; 65 (14): 6450–6458.36. Kawai H., Ishii A., Washiya K. et al. Combined overexpression of EGFR and estrogen receptor alpha correlates with a poor outcome in lung cancer. Anticancer Res. 2005; 25 (6C): 4693–4698.37. Raso M.G., Behrens C., Herynk M.H. et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin. Cancer. Res. 2009; 15 (17): 5359–5368.38. Taylor A.H., Al-Azzawi F. Immunolocalisation of oestrogen receptor b in human tissues. J. Mol. Endocrinol. 2000; 24 (1): 145–155.39. Ali G., Donati V., Loggini B. et al. Different estrogen receptor beta expression in distinct histologic subtypes of lung adenocarcinoma. Hum. Pathol. 2008; 39 (10): 1465–1473.40. Yang M.H. Estrogen receptor in female lung carcinoma. Zhonghua Jie He He Hu Xi Za Zhi. 1992; 15 (3): 138–140, 189.41. Canver C.C., Memoli V.A., Vanderveer P.L. et al. Sex hormone receptors in non-small-cell lung cancer in human beings. J. Thorac. Cardiovasc. Surg. 1994; 108 (1): 153–157.42. Bogush T.A., Shaturova A.S., Dudko E.A. et al. Sposob immunofluorestsentnogo analiza estrogenovykh retseptorov v solidnykh opukholyakh cheloveka. Reshenie o vydache patenta na izobretenie ot 04.04.2011, zayavka № 2010131313/15(044351) ot 27.07.10 [Method of Iimmunofluorescence Analysis of Estrogen Receptors in Human Solid Tumors. Decision on granting invention patent dated 04.04.2011, application № 2010131313/15 (044351) dated 07.27.10].43. Barkhem T., Carlsson B., Nilsson Y. et al. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol. 1998; 54 (1): 105–112.