jsmsJournal of Siberian Medical SciencesJournal of Siberian Medical Sciences2542-1174Federal state budgetary educational institution of higher education "Novosibirsk state medical university" of Ministry of Health of the Russian Federation (FSBEI HE NSMU MOH Russia)10.31549/2542-1174-2019-4-62-74jsms-593Research ArticleСтатьиСвязь GATA3, FOXA1, ELF5 с клинико-морфологическими параметрами люминального рака молочной железыLink between GATA3, FOXA1, ELF5 and clinicopathologic parameters of luminal breast cancerВторушинС. В.VtorushinS. V.

Вторушин Сергей Владимирович — д-р мед. наук, доцент, профессор кафедры патологической анатомии

заведующий патолого-анатомическим отделением клиник

ведущий научный сотрудник отделения общей и молекулярной патологии НИИ онкологии

Vtorushin Sergey Vladimirovich — Dr. Sci. (Med.), Associate Professor, Professor of the Pathology Department, Siberian State Medical University (Tomsk); Head of the Pathology Division of the Clinics

Leading Researcher, Pathology Department

ВасильченкоД. В.VasilchenkoD. V.

Васильченко Дмитрий Владимирович — ассистент кафедры патологической анатомии ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России (Томск); врач-патологоанатом патолого-анатомического отделения клиник

634050, г. Томск, Московский тракт, 2

Vasilchenko Dmitriy Vladimirovich — Assistant Professor of the Pathology Department

Pathologist of the Pathology Division of the Clinics

vasilchenkodmitry1991@gmail.comКрахмальН. В.Krakhmal’N. V.

Крахмаль Надежда Валерьевна — канд. мед. наук, доцент кафедры патологической анатомии

врачпатологоанатом патолого-анатомического отделения клиник

Krakhmal’ Nadezhda Valeryevna — Cand. Sci. (Med.), Associate Professor of the Pathology Department

Pathologist of the Pathology Division of the Clinics

ПаталякС. В.PatalyakS. V.

Паталяк Станислав Викторович — канд. мед. наук, заведующий онкологическим отделением дневного стационара

Patalyak Stanislav Victorovich — Cand. Sci (Med.), Head of Oncology Department of Day Hospital

НИИ онкологии ФГБНУ «Томский национальный исследовательский медицинский центр Российской академии наук»; ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава РоссииРоссияCancer Research Institute; Siberian State Medical UniversityRussian FederationФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава РоссииРоссияSiberian State Medical UniversityRussian FederationНИИ онкологии ФГБНУ «Томский национальный исследовательский медицинский центр Российской академии наук»РоссияCancer Research InstituteRussian Federation201923122019046274Copyright © Вторушин С.В., Васильченко Д.В., Крахмаль Н.В., Паталяк С.В., 20192019Вторушин С.В., Васильченко Д.В., Крахмаль Н.В., Паталяк С.В.Vtorushin S.V., Vasilchenko D.V., Krakhmal’ N.V., Patalyak S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://jsms.elpub.ru/jour/article/view/593

В настоящее время актуальным является изучение молекулярно-биологических факторов, играющих роль в прогнозе рака молочной железы (РМЖ). Большой интерес представляет анализ в опухоли транскрипционных факторов GATА3, FOXA1, ELF5, участвующих в дифференцировке эпителия молочной железы, а также в патогенезе РМЖ и механизмах опухолевой прогрессии.

В исследовании, посвященном изучению экспрессии транскрипционных факторов в зависимости от клинико-морфологических характеристик РМЖ, участвовала 101 пациентка (возраст от 30 лет до 81 года, средний возраст 54.9 ± 10.4 г.) с карциномой молочной железы (TT1–4N1–3M0). Критерии включения: люминальный РМЖ, отсутствие предоперационного лечения. Критерий исключения — IV стадия заболевания. Анализировались экспрессионные характеристики исследуемых маркеров в связи с различными клинико-морфологическими параметрами узла новообразования. Выявлено, что негативная экспрессия ELF5 ассоциирована с большим размером новообразования. Экспрессия GATА3, FOXA1 ниже у пациенток с негативной экспрессией к рецепторам прогестерона. Резко выраженная экспрессия ELF5 связана с феноменом ретракции. Характер экспрессии изучаемых маркеров ассоциирован с развитием лимфогенного метастазирования.

Таким образом, экспрессионные характеристики GATА3, FOXA1 и ELF5 могут быть полезными в качестве дополнительных прогностических факторов, используемых для оценки риска лимфогенного метастазирования.

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

Currently relevant is the study of molecular biological factors that play a role in the prognosis of breast cancer (BC). Of great interest is the analysis of the transcription factors GATА3, FOXA1, ELF5 involved in differentiation of the mammary gland epithelium, as well as in the pathogenesis of BC and the mechanisms of tumor progression.

101 patients (age from 30 years to 81 years, mean age 54.9 ± 10.4 years) with breast carcinoma (T1–4N1–3M0) participated in the study of transcription factors expression depending on clinical and morphological characteristics of BC. Inclusion criteria: luminal breast cancer, no preoperative treatment. The exclusion criterion is stage IV disease. The expression characteristics of the studied markers in the context of different clinical and morphological parameters of the neoplasm node were analyzed. Negative expression of ELF5 was found to be associated with a large tumor size. Expression of GATА3, FOXA1 is lower in patients with negative expression to progesterone receptors. The pronounced expression of ELF5 is associated with the phenomenon of retraction. The character of expression of the studied markers is associated with the development of lymphogenic metastasis.

Thus, the expression characteristics of GATА3, FOXA1 and ELF5 may be useful as additional prognostic factors used to assess the risk of lymphogenic metastasis.

Conflict of interest. The authors declare no conflict of interest.

люминальный рак молочной железыфакторы транскрипции GATA3FOXA1ELF5феномен ретракциилимфогенное метастазированиеluminal breast cancerGATA3FOXA1ELF5 transcription factorsretraction phenomenonlymph nodes metastasisReferencesЗлокачественные новообразования в России в 2017 году (заболеваемость и смертность) / под ред. А.Д. Каприна, В.В. Старинского, Г.В. Петровой. М., 2018. С. 4–6.Kaprin A.D., Starinsky V.V., Petrova G.V. (eds.) (2017). Malignant Neoplasms in Russia in 2017 (Morbidity and Mortality). Moscow, 2018, pp. 4–6. In Russ.Cancer Today: Cancer Fact Sheets // International Agency for Research on Cancer. World Health Organization. 2018. URL: http://gco.iarc.fr/today/ fact-sheets-cancers. Дата обращения: 10.08.2018.Cancer Today: Cancer Fact Sheets (2018). International Agency for Research on Cancer. World Health Organization. Retrieved Aug 10, 2018 from http:// gco.iarc.fr/today/fact-sheets-cancers.Волченко А.А., Пак Д.Д., Усов Ф.Н., Фетисова Е.Ю. Современные возможности редукционной маммопластики при органосохраняющем лечении больных раком молочной железы // Вестн. РОНЦ им. Н.Н. Блохина РАМН. 2012. Т. 23, № 4. С. 12–16.Volchenko A.A., Pak D.D., Usov F.N., Fetisova E.Yu. (2012). Current state of reduction mammaplasty in conservational surgery for breast cancer. Journal of N.N. Blokhin Russian Cancer Research Center, 23, 4, 12–16.Wang L., Guyatt G.H., Kennedy S.A. et al. Predictors of persistent pain after breast cancer surgery: a systematic review and meta-analysis of observational studies // CMAJ. 2016. Vol. 188 (14). E352–E361. doi: 10.1503/cmaj.151276.Wang L., Guyatt G.H., Kennedy S.A. et al. (2016). Predictors of persistent pain after breast cancer surgery: a systematic review and meta-analysis of observational studies. CMAJ, 188 (14), E352–E361. doi: 10.1503/cmaj.151276.Bernardo G.M., Keri R.A. FOXA1: a transcription factor with parallel functions in development and cancer // Biosci. Rep. 2012. Vol. 32 (2). P. 113–130. doi: 10.1042/BSR20110046.Bernardo G.M., Keri R.A. (2012). FOXA1: a transcription factor with parallel functions in development and cancer. Biosci. Rep., 32 (2), 113–130. doi: 10.1042/BSR20110046.Chivukula M., Picarsic J., Bulusu G. et al. Prognostic signifi cance of transcription factors FOXA1 and GATA-3 in ductal carcinoma in situ in terms of recurrence and estrogen receptor status // J. Cancer Metastasis Treat. 2015. Vol. 1. P. 84–89. doi: 10.4103/2394-4722.157600.Chivukula M., Picarsic J., Bulusu G. et al. (2015). Prognostic signifi cance of transcription factors FOXA1 and GATA-3 in ductal carcinoma in situ in terms of recurrence and estrogen receptor status. J. Cancer Metastasis Treat., 1, 84–89. doi: 10.4103/2394- 4722.157600.Wang C.C., Jamal L., Janes K.A. Normal morphogenesis of epithelial tissues and progression of epithelial tumors // Wiley Interdiscip. Rev. Syst. Biol. Med. 2012. Vol. 4 (1). P. 51–78. doi: 10.1002/wsbm.159.Wang C.C., Jamal L., Janes K.A. (2012). Normal morphogenesis of epithelial tissues and progression of epithelial tumors. Wiley Interdiscip. Rev. Syst. Biol. Med., 4 (1), 51–78. doi: 10.1002/wsbm.159.Asselin-Labat M.L., Sutherland K.D., Vaillant F. et al. Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14 // Mol. Cell. Biol. 2011. Vol. 31 (22). P. 4609–4622. doi: 10.1128/MCB.05766-11.Asselin-Labat M.L., Sutherland K.D., Vaillant F. et al. (2011). Gata-3 negatively regulates the tumorinitiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14. Mol. Cell. Biol., 31 (22), 4609–4622. doi: 10.1128/MCB.05766-11.Tkocz D., Crawford N.T., Buckley N.E. et al. BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers // Oncogene. 2012. Vol. 31 (32). P. 3667–3678. doi: 10.1038/ onc.2011.531.Tkocz D., Crawford N.T., Buckley N.E. et al. (2012). BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers. Oncogene, 31 (32), 3667–3678. doi: 10.1038/onc.2011.531.Ciriello G., Gatza M.L., Beck A.H. et al. Comprehensive molecular portraits of invasive lobular breast cancer // Cell. 2015. Vol. 163 (2). P. 506–519. doi: 10.1016/j.cell.2015.09.033.Ciriello G., Gatza M.L., Beck A.H. et al. (2015). Comprehensive molecular portraits of invasive lobular breast cancer. Cell, 63 (2), 506–519. doi: 10.1016/j. cell.2015.09.033.Mertins P., Mani D.R., Ruggles K.V. et al. Proteogenomics connects somatic mutations to signalling in breast cancer // Nature. 2016. Vol. 534 (7605). P. 55– 62. doi: 10.1038/nature18003.Mertins P., Mani D.R., Ruggles K.V. et al. (2016). Proteogenomics connects somatic mutations to signalling in breast cancer. Nature, 534 (7605), 55–62. doi: 10.1038/nature18003.Park C., Yoon K.A., Kim J. et al. Integrative molecular profi ling identifi es a novel cluster of estrogen receptor-positive breast cancer in very young women // Cancer Sci. 2019. Vol. 110 (5). P. 1760–1770. doi: 10.1111/cas.13982.Park C., Yoon K.A., Kim J. et al. (2019). Integrative molecular profi ling identifi es a novel cluster of estrogen receptor-positive breast cancer in very young women. Cancer Sci., 110 (5), 1760–1770. doi: 10.1111/ cas.13982.Mehra R., Varambally S., Ding L. et al. Identifi cation of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis // Cancer Res. 2005. Vol. 65 (24). P. 11259–11264. doi: 10.1158/0008- 5472.CAN-05-2495.Mehra R., Varambally S., Ding L. et al. (2005). Identifi cation of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. Cancer Res., 65 (24), 11259–11264. doi: 10.1158/0008-5472. CAN-05-2495.Yoon N.K., Maresh E.L., Shean D. et al. Higher levels of GATA3 predict better survival in women with breast cancer // Hum. Pathol. 2010. Vol. 41 (12). P. 1794–1801. doi: 10.1016/j.humpath.2010.06.010.Yoon N.K., Maresh E.L., Shean D. et al. (2010). Higher levels of GATA3 predict better survival in women with breast cancer. Hum. Pathol., 41 (12), 1794–1801. doi: 10.1016/j.humpath.2010.06.010.Gulbahce H.E., Sweeney C., Surowiecka M. et al. Signifi cance of GATA-3 expression in outcomes of patients with breast cancer who received systemic chemotherapy and/or hormonal therapy and clinicopathologic features of GATA-3-positive tumors // Hum. Pathol. 2013. Vol. 44 (11). P. 2427–2431. doi: 10.1016/j. humpath.2013.05.022.Gulbahce H.E., Sweeney C., Surowiecka M. et al. (2013). Signifi cance of GATA-3 expression in outcomes of patients with breast cancer who received systemic chemotherapy and/or hormonal therapy and clinicopathologic features of GATA-3-positive tumors. Hum. Pathol., 44 (11), 2427–2431. doi: 10.1016/j.humpath.2013.05.022.Fang S.H., Chen Y., Weigel R.J. GATA-3 as a marker of hormone response in breast cancer // J. Surg. Res. 2009. Vol. 157 (2). P. 290–295. doi: 10.1016/j. jss.2008.07.015.Fang S.H., Chen Y., Weigel R.J. (2009). GATA-3 as a marker of hormone response in breast cancer. J. Surg. Res., 157 (2), 290–295. doi: 10.1016/j.jss.2008.07.015.Voduc D., Cheang M., Nielsen T. GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value // Cancer Epidemiol. Biomarkers Prev. 2008. Vol. 17 (2). P. 365–373. doi: 10.1158/1055-9965.EPI-06-1090.Voduc D., Cheang M., Nielsen T. (2008). GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol. Biomarkers Prev., 17 (2), 365–373. doi: 10.1158/1055-9965.EPI-06-1090.Rangel N., Fortunati N., Osella-Abate S. et al. FOXA1 and AR in invasive breast cancer: new fi ndings on their co-expression and impact on prognosis in ERpositive patients // BMC Cancer. 2018. Vol. 18 (1). P. 703. doi: org/10.1186/s12885-018-4624-y.Rangel N., Fortunati N., Osella-Abate S. et al. (2018). FOXA1 and AR in invasive breast cancer: new fi ndings on their co-expression and impact on prognosis in ER-positive patients. BMC Cancer, 18 (1), 703. doi: org/10.1186/s12885-018-4624-y.Hu Q., Luo Z., Xu T. et al. FOXA1: a promising prognostic marker in breast cancer // Asian Pacifi c J. Cancer Prev. 2014. Vol. 15 (1). P. 11–16. doi: 10.7314/ APJCP.2014.15.1.11.Hu Q., Luo Z., Xu T. et al. (2014). FOXA1: a promising prognostic marker in breast cancer. Asian Pacifi c J. Cancer Prev., 15 (1), 11–16. doi: 10.7314/ APJCP.2014.15.1.11.Williamson E.A., Wolf I., O’Kelly J. et al. BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1) // Oncogene. 2006. Vol. 25 (9). P. 1391–1399. doi: 10.1038/ sj.onc.1209170.Williamson E.A., Wolf I., O’Kelly J. et al. (2006). BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1). Oncogene, 25 (9), 1391–1399. doi: 10.1038/ sj.onc.1209170.De Lara S., Nyqvist J., Werner Rönnerman E. et al. The prognostic relevance of FOXA1 and Nestin expression in breast cancer metastases: a retrospective study of 164 cases during a 10-year period (2004–2014) // BMC Cancer. 2019. Vol. 19 (1): 187. doi: org/10.1186/ s12885-019-5373-2.De Lara S., Nyqvist J., Werner Rönnerman E. et al. (2019). The prognostic relevance of FOXA1 and Nestin expression in breast cancer metastases: a retrospective study of 164 cases during a 10- year period (2004–2014). BMC Cancer, 19 (1), 187. doi: org/10.1186/s12885-019-5373-2.Choi Y.S., Chakrabarty R., Escamilla-Hernandez R., Sinha S. Elf5 conditional knockout mice reveal its role as a master regulator in mammary alveolar development: failure of Stat5 activation and functional differentiation in the absence of Elf5 // Dev. Biol. 2009. Vol. 329 (2). P. 227–241. doi: 10.1016/j.ydbio.2009.02.032.Choi Y.S., Chakrabarty R., Escamilla-Hernandez R., Sinha S. (2009). Elf5 conditional knockout mice reveal its role as a master regulator in mammary alveolar development: failure of Stat5 activation and functional differentiation in the absence of Elf5. Dev. Biol., 329 (2), 227–241. doi: 10.1016/j.ydbio.2009.02.032.Oakes S.R., Naylor M.J., Asselin-Labat M.L. et al. The Ets transcription factor Elf5 specifi es mammary alveolar cell fate // Genes Dev. 2008. Vol. 22 (5). P. 581–586. doi: 10.1101/gad.1614608.Oakes S.R., Naylor M.J., Asselin-Labat M.L. et al. (2008). The Ets transcription factor Elf5 specifi es mammary alveolar cell fate. Genes Dev., 22 (5), 581– 586. doi: 10.1101/gad.1614608.Kalyuga M., Callego-Ortega D., Lee H.J. et al. ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer // PLoS Biol. 2012. Vol. 10 (12): e1001461. doi: 10.1371/journal.pbio.1001461.Kalyuga M., Callego-Ortega D., Lee H.J. et al. (2012). ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer. PLoS Biol., 10 (12), e1001461. doi: 10.1371/journal.pbio.1001461.Omata F., McNamara K.M., Suzuki K. et al. Effect of the normal mammary differentiation regulator ELF5 upon clinical outcomes of triple negative breast cancers patients // Breast Cancer. 2018. Vol. 25 (4). P. 489–496. doi: org/10.1007/s12282-018-0842-z.Omata F., McNamara K.M., Suzuki K. et al. (2018). Effect of the normal mammary differentiation regulator ELF5 upon clinical outcomes of triple negative breast cancers patients. Breast Cancer, 25 (4), 489– 496. doi: org/10.1007/s12282-018-0842-zChakrabarti R., Hwang J., Andres Blanco H. et al. Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2 // Nat. Cell Biol. 2012. Vol. 14 (11). P. 1212–1222. doi: 10.1038/ ncb2607.Chakrabarti R., Hwang J. Andres Blanco H. et al. (2012). Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat. Cell Biol., 14 (11), 1212–1222. doi: 10.1038/ncb2607.Acs G., Paragh G., Rakosy Z., Laronga C., Zhang P.J. The extent of retraction clefts correlates with lymphatic vessel density and VEGF-C expression and predicts nodal metastasis and poor prognosis in earlystage breast carcinoma // Mod. Pathol. 2012. Vol. 25 (2). P. 163–177. doi: 10.1038/modpathol.2011.Acs G., Paragh G., Rakosy Z., Laronga C., Zhang P.J. (2012). The extent of retraction clefts correlates with lymphatic vessel density and VEGF-C expression and predicts nodal metastasis and poor prognosis in early-stage breast carcinoma. Mod. Pathol., 25 (2), 163–177. doi: 10.1038/modpathol.2011.

The authors declare that there are no conflicts of interest present.