Top

Published in:

01-07-2012 | Preclinical Study

Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients

Authors: Jun Tang, Rong Deng, Rong-Zhen Luo, Guo-Ping Shen, Mu-Yan Cai, Zi-Ming Du, Shan Jiang, Ming-Tian Yang, Jian-Hua Fu, Xiao-Feng Zhu

Published in: Breast Cancer Research and Treatment | Issue 2/2012

Abstract

ULK1 plays an important role in autophagy which is widely involved in the development of breast cancer. However, the function and expression of ULK1 in human breast cancer is still scarcely explored. In this study, we showed that the mRNA and protein levels of ULK1 decreased in 10 of 14 (71.4 %) breast cancer tissues, compared with matched normal tissues. Furthermore, immunohistochemical staining of ULK1 was performed on the tissue microarray containing 298 non-metastatic invasive breast primary cancer tissues and 73 matched adjacent noncancerous tissues. 70.1 % breast cancer specimens displayed none to weak staining of ULK1, however, 78.1 % adjacent noncancerous specimens showed moderate to strong staining of ULK1. Statistical analysis revealed that ULK1 expression was negatively correlated with tumor size (r = −0.176, P = 0.002), lymph node status (r = −0.115, P = 0.048), and pathological stage (r = −0.177, P = 0.002). The log-rank test showed that patients with lower level of ULK1 had a significant shorter distant metastasis-free survival time (P = 0.008) and cancer-related survival time (P = 0.008). Multivariate Cox regression analysis found that ULK1 expression was recognized as an independent prognostic factor (P = 0.034). In addition, a significant positive correlation between expression of ULK1 and LC3A (r = 0.401, P < 0.001), and a significant negative correlation between expression of ULK1 and p62 (r = −0.226, P < 0.001) were observed in our breast cancer cohort. These findings suggest that decreased expression of ULK1 is associated with breast cancer progression, together with closely related to decreased autophagic capacity. ULK1 also may be used as a novel prognostic biomarker for breast cancer patients.

Available only for authorised users

Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O’Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ (2000) Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124(7):966–978. doi:10.1043/0003-9985 PubMed

Stark A, Hulka BS, Joens S, Novotny D, Thor AD, Wold LE, Schell MJ, Melton LJ 3rd, Liu ET, Conway K (2000) HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer. J Clin Oncol 18(2):267–274PubMed

Rakha EA, Reis-Filho JS, Ellis IO (2010) Combinatorial biomarker expression in breast cancer. Breast Cancer Res Treat 120(2):293–308PubMedCrossRef

Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN (2011) Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat 130(2):437–447PubMedCrossRef

Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY, Wu J, Yuan J, Zhang HZ, Zeng MS, Li M (2008) Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res 14(11):3319–3326PubMedCrossRef

Zhao M, Klionsky DJ (2011) AMPK-dependent phosphorylation of ULK1 induces autophagy. Cell Metab 13(2):119–120PubMedCrossRef

Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075PubMedCrossRef

Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290(5497):1717–1721PubMedCrossRef

Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell’antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25(7):717–729PubMedCrossRef

10.

Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672–676PubMedCrossRef

11.

Karantza-Wadsworth V, White E (2007) Role of autophagy in breast cancer. Autophagy 3(6):610–613PubMed

12.

Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC, Levine B (1999) Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 59(1):59–65PubMedCrossRef

13.

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Investig 112(12):1809–1820PubMed

14.

Kuroyanagi H, Yan J, Seki N, Yamanouchi Y, Suzuki Y, Takano T, Muramatsu M, Shirasawa T (1998) Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment. Genomics 51(1):76–85PubMedCrossRef

15.

Yan J, Kuroyanagi H, Kuroiwa A, Matsuda Y, Tokumitsu H, Tomoda T, Shirasawa T, Muramatsu M (1998) Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51. Biochem Biophys Res Commun 246(1):222–227PubMedCrossRef

16.

Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N (2008) FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 181(3):497–510PubMedCrossRef

17.

Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N (2009) Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 5(7):973–979PubMedCrossRef

18.

Mercer CA, Kaliappan A, Dennis PB (2009) A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 5(5):649–662PubMedCrossRef

19.

Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22(2):132–139PubMedCrossRef

20.

Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331(6016):456–461PubMedCrossRef

21.

Shang L, Wang X (2011) AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy 7(8):924–926PubMedCrossRef

22.

Deng R, Tang J, Ma JG, Chen SP, Xia LP, Zhou WJ, Li DD, Feng GK, Zeng YX, Zhu XF (2011) PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation. Oncogene 30(8):944–955PubMedCrossRef

23.

Deng R, Tang J, Xia LP, Li DD, Zhou WJ, Wang LL, Feng GK, Zeng YX, Gao YH, Zhu XF (2009) ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of its signal pathway. Mol Cancer Ther 8(4):873–882PubMedCrossRef

24.

Zhou WJ, Deng R, Zhang XY, Feng GK, Gu LQ, Zhu XF (2009) G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells. Mol Cancer Ther 8(12):3203–3213PubMedCrossRef

25.

Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847PubMedCrossRef

26.

Jiang S, Li Y, Zhu YH, Wu XQ, Tang J, Li Z, Feng GK, Deng R, Li DD, Luo RZ, Zhang MF, Qin W, Wang X, Jia WH, Zhu XF (2011) Intensive expression of UNC-51-like kinase 1 is a novel biomarker of poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Sci 102(8):1568–1575. doi:10.1111/j.1349-7006.2011.01964.x PubMedCrossRef

27.

Sivridis E, Koukourakis MI, Zois CE, Ledaki I, Ferguson DJ, Harris AL, Gatter KC, Giatromanolaki A (2010) LC3A-positive light microscopy detected patterns of autophagy and prognosis in operable breast carcinomas. Am J Pathol 176(5):2477–2489PubMedCrossRef

28.

Rolland P, Madjd Z, Durrant L, Ellis IO, Layfield R, Spendlove I (2007) The ubiquitin-binding protein p62 is expressed in breast cancers showing features of aggressive disease. Endocr Relat Cancer 14(1):73–80PubMedCrossRef

29.

Borgquist S, Holm C, Stendahl M, Anagnostaki L, Landberg G, Jirstrom K (2008) Oestrogen receptors alpha and beta show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer. J Clin Pathol 61(2):197–203PubMedCrossRef

30.

Hayes DF, Ethier S, Lippman ME (2006) New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK. Breast Cancer Res Treat 100(2):237–238. doi:10.1007/s10549-006-9253-5 PubMedCrossRef

31.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072PubMedCrossRef

32.

Sivridis E, Koukourakis MI, Mendrinos SE, Karpouzis A, Fiska A, Kouskoukis C, Giatromanolaki A (2011) Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1. Melanoma Res 21(3):188–195PubMedCrossRef

33.

Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140(3):313–326PubMedCrossRef

34.

Giatromanolaki A, Koukourakis MI, Harris AL, Polychronidis A, Gatter KC, Sivridis E (2011) Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas. J Clin Pathol 63(10):867–872CrossRef

35.

Giatromanolaki AN, Charitoudis GS, Bechrakis NE, Kozobolis VP, Koukourakis MI, Foerster MH, Sivridis EL (2011) Autophagy patterns and prognosis in uveal melanomas. Mod Pathol 24(8):1036–1045PubMedCrossRef

36.

Karpathiou G, Sivridis E, Koukourakis MI, Mikroulis D, Bouros D, Froudarakis ME, Giatromanolaki A (2011) Light-chain 3A autophagic activity and prognostic significance in non-small cell lung carcinomas. Chest 140(1):127–134PubMedCrossRef

37.

Kirkin V, McEwan DG, Novak I, Dikic I (2009) A role for ubiquitin in selective autophagy. Mol Cell 34(3):259–269PubMedCrossRef

38.

Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, Dipaola RS, Karantza-Wadsworth V, White E (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137(6):1062–1075PubMedCrossRef

39.

Chan EY, Longatti A, McKnight NC, Tooze SA (2009) Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol 29(1):157–171PubMedCrossRef

40.

Chan EY, Kir S, Tooze SA (2007) siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem 282(35):25464–25474PubMedCrossRef

41.

Kundu M, Lindsten T, Yang CY, Wu J, Zhao F, Zhang J, Selak MA, Ney PA, Thompson CB (2008) Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112(4):1493–1502PubMedCrossRef

42.

Cheong H, Lindsten T, Wu J, Lu C, Thompson CB (2011) Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Nat Acad Sci USA 108(27):11121–11126PubMedCrossRef

43.

Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822PubMedCrossRef

44.

Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev 5(9):726–734CrossRef

45.

White EJ, Martin V, Liu JL, Klein SR, Piya S, Gomez-Manzano C, Fueyo J, Jiang H (2011) Autophagy regulation in cancer development and therapy. Am J Cancer Res 1(3):362–372PubMed

46.

Jung CH, Seo M, Otto NM, Kim DH (2011) ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 7(10):1212–1221PubMedCrossRef

47.

Gao W, Shen Z, Shang L, Wang X (2011) Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death. Cell Death Differ 18:1598–1607PubMedCrossRef

Title: Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients
Authors: Jun Tang
Rong Deng
Rong-Zhen Luo
Guo-Ping Shen
Mu-Yan Cai
Zi-Ming Du
Shan Jiang
Ming-Tian Yang
Jian-Hua Fu
Xiao-Feng Zhu
Publication date: 01-07-2012
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-012-2080-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2012

Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells

Mechanisms of cardiotoxicity associated with ErbB2 inhibitors

The influence of non-clinical patient factors on medical oncologists’ decisions to recommend breast cancer adjuvant chemotherapy

Serum cotinine and prognosis in breast cancer

Adult weight gain, fat distribution and mammographic density in Spanish pre- and post-menopausal women (DDM-Spain)

Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies

Keynote webinar | Spotlight on antibody–drug conjugates in cancer