Skip to main content
Top
Published in: Tumor Biology 6/2012

01-12-2012 | Research Article

Study on the skip metastasis of axillary lymph nodes in breast cancer and their relation with Gli1 expression

Authors: Huan Wang, Xiao-Yun Mao, Ting-Ting Zhao, Xin-Yu Zheng, Feng Jin, Ji-Guang Li

Published in: Tumor Biology | Issue 6/2012

Login to get access

Abstract

The skip metastasis (SM) of axillary lymph nodes (ALN) in breast cancer is an important phenomenon which is crucial to determine the correct choice of surgical resection. The mechanism of SM of ALN is unclear. Gli1 protein is a core epithelial-to-mesenchymal transition (EMT) regulatory factor that plays essential roles in both development and disease processes and has been associated with metastasis in carcinomas. The aim of this study was to investigate the clinicopathological characteristics of SM and evaluate the significance of Gli1 expression in breast cancer patients with metastasis of ALN. Clinicopathological data from 1,037 female breast cancer patients who underwent radical mastectomy were retrospectively reviewed. In this study, an SM was defined as level I absence but level II and/or level III involvement. The expression of Gli1 was evaluated by immunohistochemistry in 102 non-SM cases with positive nodes and 33 SM cases. In univariate analysis, we found that pN category, TNM stage, intrinsic subtypes and Gli1 expression was significant risk factor of SM. Further logistic regression analysis revealed that luminal A cases had a lower risk of SM relative to luminal B 1 (HER2 negative) cases. Further multivariate analysis revealed that Gli1 expression and numbers of positive lymph nodes were the independent factors which associated with SM. Collectively, Breast cancer with SM of ALN associated with the intrinsic subtype of the luminal B1. Gli1 expression related with the procession of breast cancer with SM, which can be used as a predictor of SM of ALN in breast cancer.
Literature
1.
go back to reference Chevinsky AH, Ferrara J, James AG, Minton JP, Young D, Farrar WB. Prospective evaluation of clinical and pathologic detection of axillary metastases in patients with carcinoma of the breast. Surgery. 1990;108(4):612–7. discussion 617–618.PubMed Chevinsky AH, Ferrara J, James AG, Minton JP, Young D, Farrar WB. Prospective evaluation of clinical and pathologic detection of axillary metastases in patients with carcinoma of the breast. Surgery. 1990;108(4):612–7. discussion 617–618.PubMed
2.
go back to reference Msuya CA, Hartveit F. Skip lesions in the axilla in breast cancer, and their association with micrometastases. Breast Cancer Res Treat. 1991;19(3):277–81.PubMedCrossRef Msuya CA, Hartveit F. Skip lesions in the axilla in breast cancer, and their association with micrometastases. Breast Cancer Res Treat. 1991;19(3):277–81.PubMedCrossRef
3.
go back to reference Senofsky GM, Moffat Jr FL, Davis K, Masri MM, Clark KC, Robinson DS, et al. Total axillary lymphadenectomy in the management of breast cancer. Arch Surg. 1991;126(11):1336–41. discussion 1341–2.PubMedCrossRef Senofsky GM, Moffat Jr FL, Davis K, Masri MM, Clark KC, Robinson DS, et al. Total axillary lymphadenectomy in the management of breast cancer. Arch Surg. 1991;126(11):1336–41. discussion 1341–2.PubMedCrossRef
4.
go back to reference Veronesi U, Rilke F, Luini A, Sacchini V, Galimberti V, Campa T, et al. Distribution of axillary node metastases by level of invasion. An analysis of 539 cases. Cancer. 1987;59(4):682–7.PubMedCrossRef Veronesi U, Rilke F, Luini A, Sacchini V, Galimberti V, Campa T, et al. Distribution of axillary node metastases by level of invasion. An analysis of 539 cases. Cancer. 1987;59(4):682–7.PubMedCrossRef
6.
go back to reference Hayashida T, Jinno H, Kitagawa Y, Kitajima M. Cooperation of cancer stem cell properties and epithelial–mesenchymal transition in the establishment of breast cancer metastasis. J Oncol. 2011;2011:591427. doi:10.1155/2011/591427.PubMedCrossRef Hayashida T, Jinno H, Kitagawa Y, Kitajima M. Cooperation of cancer stem cell properties and epithelial–mesenchymal transition in the establishment of breast cancer metastasis. J Oncol. 2011;2011:591427. doi:10.​1155/​2011/​591427.PubMedCrossRef
7.
go back to reference Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1(6–7):338–51. doi:10.1002/emmm.200900039.PubMedCrossRef Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1(6–7):338–51. doi:10.​1002/​emmm.​200900039.PubMedCrossRef
9.
10.
go back to reference Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R. The output of Hedgehog signaling is controlled by the dynamic association between suppressor of fused and the Gli proteins. Genes Dev. 2010;24(7):670–82. doi:10.1101/gad.1902910.PubMedCrossRef Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R. The output of Hedgehog signaling is controlled by the dynamic association between suppressor of fused and the Gli proteins. Genes Dev. 2010;24(7):670–82. doi:10.​1101/​gad.​1902910.PubMedCrossRef
12.
go back to reference Kok LF, Lee MY, Tyan YS, Wu TS, Cheng YW, Kung MF, et al. Comparing the scoring mechanisms of p16INK4a immunohistochemistry based on independent nucleic stains and independent cytoplasmic stains in distinguishing between endocervical and endometrial adenocarcinomas in a tissue microarray study. Arch Gynecol Obstet. 2010;281(2):293–300. doi:10.1007/s00404-009-1094-0.PubMedCrossRef Kok LF, Lee MY, Tyan YS, Wu TS, Cheng YW, Kung MF, et al. Comparing the scoring mechanisms of p16INK4a immunohistochemistry based on independent nucleic stains and independent cytoplasmic stains in distinguishing between endocervical and endometrial adenocarcinomas in a tissue microarray study. Arch Gynecol Obstet. 2010;281(2):293–300. doi:10.​1007/​s00404-009-1094-0.PubMedCrossRef
13.
go back to reference Koo CL, Kok LF, Lee MY, Wu TS, Cheng YW, Hsu JD, et al. Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. J Transl Med. 2009;7:25. doi:10.1186/1479-5876-7-25.PubMedCrossRef Koo CL, Kok LF, Lee MY, Wu TS, Cheng YW, Hsu JD, et al. Scoring mechanisms of p16INK4a immunohistochemistry based on either independent nucleic stain or mixed cytoplasmic with nucleic expression can significantly signal to distinguish between endocervical and endometrial adenocarcinomas in a tissue microarray study. J Transl Med. 2009;7:25. doi:10.​1186/​1479-5876-7-25.PubMedCrossRef
14.
go back to reference Hatanaka Y, Hashizume K, Kamihara Y, Itoh H, Tsuda H, Osamura RY, et al. Quantitative immunohistochemical evaluation of HER2/neu expression with HercepTestTM in breast carcinoma by image analysis. Pathol Int. 2001;51(1):33–6.PubMedCrossRef Hatanaka Y, Hashizume K, Kamihara Y, Itoh H, Tsuda H, Osamura RY, et al. Quantitative immunohistochemical evaluation of HER2/neu expression with HercepTestTM in breast carcinoma by image analysis. Pathol Int. 2001;51(1):33–6.PubMedCrossRef
16.
go back to reference Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St. Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol. 2011;22(8):1736–47. doi:10.1093/annonc/mdr304.PubMedCrossRef Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St. Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol. 2011;22(8):1736–47. doi:10.​1093/​annonc/​mdr304.PubMedCrossRef
17.
go back to reference Grube BJ, Giuliano AE. Observation of the breast cancer patient with a tumor-positive sentinel node: implications of the ACOSOG Z0011 trial. Semin Surg Oncol. 2001;20(3):230–7.PubMedCrossRef Grube BJ, Giuliano AE. Observation of the breast cancer patient with a tumor-positive sentinel node: implications of the ACOSOG Z0011 trial. Semin Surg Oncol. 2001;20(3):230–7.PubMedCrossRef
18.
go back to reference Gaglia P, Bussone R, Caldarola B, Lai M, Jayme A, Caldarola L. The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer. A multifactorial analysis. Eur J Cancer Clin Oncol. 1987;23(6):849–54.PubMedCrossRef Gaglia P, Bussone R, Caldarola B, Lai M, Jayme A, Caldarola L. The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer. A multifactorial analysis. Eur J Cancer Clin Oncol. 1987;23(6):849–54.PubMedCrossRef
23.
go back to reference Heitz F, Harter P, Lueck HJ, Fissler-Eckhoff A, Lorenz-Salehi F, Scheil-Bertram S, et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases. Eur J Cancer. 2009;45(16):2792–8. doi:10.1016/j.ejca.2009.06.027.PubMedCrossRef Heitz F, Harter P, Lueck HJ, Fissler-Eckhoff A, Lorenz-Salehi F, Scheil-Bertram S, et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases. Eur J Cancer. 2009;45(16):2792–8. doi:10.​1016/​j.​ejca.​2009.​06.​027.PubMedCrossRef
24.
go back to reference Van Calster B, Vanden Bempt I, Drijkoningen M, Pochet N, Cheng J, Van Huffel S, et al. Axillary lymph node status of operable breast cancers by combined steroid receptor and HER-2 status: triple positive tumours are more likely lymph node positive. Breast Cancer Res Treat. 2009;113(1):181–7. doi:10.1007/s10549-008-9914-7.PubMedCrossRef Van Calster B, Vanden Bempt I, Drijkoningen M, Pochet N, Cheng J, Van Huffel S, et al. Axillary lymph node status of operable breast cancers by combined steroid receptor and HER-2 status: triple positive tumours are more likely lymph node positive. Breast Cancer Res Treat. 2009;113(1):181–7. doi:10.​1007/​s10549-008-9914-7.PubMedCrossRef
25.
go back to reference Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008;26(14):2373–8. doi:10.1200/jco.2007.14.4287.PubMedCrossRef Nguyen PL, Taghian AG, Katz MS, Niemierko A, Abi Raad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008;26(14):2373–8. doi:10.​1200/​jco.​2007.​14.​4287.PubMedCrossRef
27.
go back to reference Kwon YJ, Hurst DR, Steg AD, Yuan K, Vaidya KS, Welch DR, et al. Gli1 enhances migration and invasion via up-regulation of MMP-11 and promotes metastasis in ERalpha negative breast cancer cell lines. Clin Exp Metastasis. 2011;28(5):437–49. doi:10.1007/s10585-011-9382-z.PubMedCrossRef Kwon YJ, Hurst DR, Steg AD, Yuan K, Vaidya KS, Welch DR, et al. Gli1 enhances migration and invasion via up-regulation of MMP-11 and promotes metastasis in ERalpha negative breast cancer cell lines. Clin Exp Metastasis. 2011;28(5):437–49. doi:10.​1007/​s10585-011-9382-z.PubMedCrossRef
29.
go back to reference Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 2007;67(14):6981–6. doi:10.1158/0008-5472.can-07-0491.PubMedCrossRef Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 2007;67(14):6981–6. doi:10.​1158/​0008-5472.​can-07-0491.PubMedCrossRef
31.
Metadata
Title
Study on the skip metastasis of axillary lymph nodes in breast cancer and their relation with Gli1 expression
Authors
Huan Wang
Xiao-Yun Mao
Ting-Ting Zhao
Xin-Yu Zheng
Feng Jin
Ji-Guang Li
Publication date
01-12-2012
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2012
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-012-0455-7

Other articles of this Issue 6/2012

Tumor Biology 6/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine