Site-specific metabolic phenotypes in metastatic breast cancer

Journal of Translational Medicine

Ja Seung Koo¹  Woo Hee Jung¹  Hye Min Kim¹ 

[1] Department of Pathology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea

关键词: Metastasis;    Metabolism;    Breast;   

Others  :  1146581
DOI  :  10.1186/s12967-014-0354-3

 received in 2014-08-27, accepted in 2014-12-03,  发布年份 2014

【 摘 要 】

Background

The purpose of this study was to examine the expression of metabolism-related proteins according to metastatic site in metastatic breast cancer and to assess the implication of site-specific differential expression.

Methods

A tissue microarray containing 162 cases of metastatic breast cancer (52 lung metastasis, 47 bone metastasis, 39 brain metastasis, and 24 liver metastasis) was constructed. It was subject to immunohistochemical staining of the following proteins: Glycolysis-related: Glut-1, hexolinase II, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; glutaminolysis-related: glutaminase (GLS) 1, glutamate dehydrogenase (GDH), and amino acid transporter (ASCT) 2; mitochondrial metabolism-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB; and serine/glycine metabolism related: phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), phosphoserine phosphatase (PSPH), glycine decarboxylase (GLDC), and serine hydroxymethyltransferase (SHMT).

Results

The expression levels of glycolysis-related-proteins (Glut-1, hexokinase II, CAIX, and MCT4) differed according to metastatic site, with higher expression seen in the brain and lower expression in the bone and liver (p < 0.001, 0.001, 0.009, and <0.001, respectively). Differences in metabolic phenotype were analyzed according to metastasis site. Glycolysis type was most frequently encountered in the brain and lung (p < 0.001). In univariate analysis, the factors associated with shorter overall survival were CAIX positivity (p = 0.044), PSPH positivity (p = 0.045), and SHMT1 positivity (p = 0.002), as well as serine/glycine type (p = 0.041).

Conclusions

Differences in metabolic features according to metastatic site were seen in metastatic breast cancer, with the glycolysis phenotype found predominantly in the brain and lung and the non-glycolysis phenotype in the bone and liver.

【 授权许可】

   
2014 Kim et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS: Breast cancer metastasis to the central nervous system. Am J Pathol 2005, 167:913-920.
• [2]Woodhouse EC, Chuaqui RF, Liotta LA: General mechanisms of metastasis. Cancer 1997, 80:1529-1537.
• [3]Abali H, Celik I: High incidence of central nervous system involvement in patients with breast cancer treated with epirubicin and docetaxel. Am J Clin Oncol 2002, 25:632-633.
• [4]Colleoni M, O’Neill A, Goldhirsch A, Gelber RD, Bonetti M, Thurlimann B, Price KN, Castiglione-Gertsch M, Coates AS, Lindtner J, Collins J, Senn HJ, Cavalli F, Forbes J, Gudgeon A, Simoncini E, Cortes-Funes H, Veronesi A, Fey M, Rudenstam CM: Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol 2000, 18:3925-3935.
• [5]Evans AJ, James JJ, Cornford EJ, Chan SY, Burrell HC, Pinder SE, Gutteridge E, Robertson JF, Hornbuckle J, Cheung KL: Brain metastases from breast cancer: identification of a high-risk group. Clin Oncol (R Coll Radiol) 2004, 16:345-349.
• [6]Gaedcke J, Traub F, Milde S, Wilkens L, Stan A, Ostertag H, Christgen M, von Wasielewski R, Kreipe HH: Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod Pathol 2007, 20:864-870.
• [7]Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, Crowe JP, Choueiri TK, Dawson AE, Budd GT, Tubbs RR, Casey G, Weil RJ: Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR. Am J Surg Pathol 2006, 30:1097-1104.
• [8]Lorincz T, Toth J, Badalian G, Timar J, Szendroi M: HER-2/neu genotype of breast cancer may change in bone metastasis. Pathol Oncol Res 2006, 12:149-152.
• [9]Nicolson GL: Organ specificity of tumor metastasis: role of preferential adhesion, invasion and growth of malignant cells at specific secondary sites. Cancer Metastasis Rev 1988, 7:143-188.
• [10]Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1889, 1:571-572.
• [11]Hasebe T, Imoto S, Yokose T, Ishii G, Iwasaki M, Wada N: Histopathologic factors significantly associated with initial organ-specific metastasis by invasive ductal carcinoma of the breast: a prospective study. Hum Pathol 2008, 39:681-693.
• [12]Wei B, Wang J, Bourne P, Yang Q, Hicks D, Bu H, Tang P: Bone metastasis is strongly associated with estrogen receptor-positive/progesterone receptor-negative breast carcinomas. Hum Pathol 2008, 39:1809-1815.
• [13]Warburg O: On the origin of cancer cells. Science 1956, 123:309-314.
• [14]Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E: Energy metabolism in tumor cells. FEBS J 2007, 274:1393-1418.
• [15]Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, Kafri R, Kirschner MW, Clish CB, Mootha VK: Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 2012, 336:1040-1044.
• [16]Bhargava R, Beriwal S, Striebel JM, Dabbs DJ: Breast cancer molecular class ERBB2: preponderance of tumors with apocrine differentiation and expression of basal phenotype markers CK5, CK5/6, and EGFR. Appl Immunohistochem Mol Morphol 2010, 18:113-118.
• [17]Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM: Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011, 476:346-350.
• [18]Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, Bhakoo KK, Jayapal SR, Nichane M, Yu Q, Ahmed DA, Tan C, Sing WP, Tam J, Thirugananam A, Noghabi MS, Pang YH, Ang HS, Mitchell W, Robson P, Kaldis P, Soo RA, Swarup S, Lim EH, Lim B: Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 2012, 148:259-272.
• [19]Dang CV, Hamaker M, Sun P, Le A, Gao P: Therapeutic targeting of cancer cell metabolism. J Mol Med (Berl) 2011, 89:205-212.
• [20]Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991, 19:403-410.
• [21]Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, et al.: American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010, 28:2784-2795.
• [22]Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007, 25:118-145.
• [23]Won KY, Kim GY, Kim YW, Song JY, Lim SJ: Clinicopathologic correlation of beclin-1 and bcl-2 expression in human breast cancer. Hum Pathol 2010, 41:107-112.
• [24]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, 22:1736-1747.
• [25]Pinheiro C, Sousa B, Albergaria A, Paredes J, Dufloth R, Vieira D, Schmitt F, Baltazar F: GLUT1 and CAIX expression profiles in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol 2011, 26:1279-1286.
• [26]Choi J, Jung WH, Koo JS: Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. Pathobiology 2013, 80:41-52.
• [27]Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabieres C, Janni W, Messina C, Paoletti C, Muller V, Hayes DF, Piccart M, Pierga JY: Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev 2013, 32:179-188.
• [28]Khatami M: Unresolved inflammation: ‘immune tsunami’ or erosion of integrity in immune-privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer. Expert Opin Biol Ther 2011, 11:1419-1432.
• [29]Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP: Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: a transcriptional informatics analysis with validation. Cell Cycle 2010, 9:2201-2219.
• [30]Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP: The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009, 8:3984-4001.
• [31]Choi J, Kim Do H, Jung WH, Koo JS: Metabolic interaction between cancer cells and stromal cells according to breast cancer molecular subtype. Breast Cancer Res 2013, 15:R78. BioMed Central Full Text
• [32]Zidan J, Dashkovsky I, Stayerman C, Basher W, Cozacov C, Hadary A: Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease. Br J Cancer 2005, 93:552-556.
• [33]Brunn Rasmussen B, Kamby C: Immunohistochemical detection of estrogen receptors in paraffin sections from primary and metastatic breast cancer. Pathol Res Pract 1989, 185:856-859.
• [34]Gomez-Fernandez C, Daneshbod Y, Nassiri M, Milikowski C, Alvarez C, Nadji M: Immunohistochemically determined estrogen receptor phenotype remains stable in recurrent and metastatic breast cancer. Am J Clin Pathol 2008, 130:879-882.
• [35]Kuukasjarvi T, Kononen J, Helin H, Holli K, Isola J: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 1996, 14:2584-2589.
• [36]Mohanti BK, Rath GK, Anantha N, Kannan V, Das BS, Chandramouli BA, Banerjee AK, Das S, Jena A, Ravichandran R, Sahi UP, Kumar R, Kapoor N, Kalia VK, Dwarakanath BS, Jain V: Improving cancer radiotherapy with 2-deoxy-D-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys 1996, 35:103-111.
• [37]Aft RL, Zhang FW, Gius D: Evaluation of 2-deoxy-D-glucose as a chemotherapeutic agent: mechanism of cell death. Br J Cancer 2002, 87:805-812.
• [38]Vullo D, Franchi M, Gallori E, Pastorek J, Scozzafava A, Pastorekova S, Supuran CT: Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides. Bioorg Med Chem Lett 2003, 13:1005-1009.
• [39]Gallagher SM, Castorino JJ, Wang D, Philp NJ: Monocarboxylate transporter 4 regulates maturation and trafficking of CD147 to the plasma membrane in the metastatic breast cancer cell line MDA-MB-231. Cancer Res 2007, 67:4182-4189.
• [40]Khatami M: Unresolved inflammation and cancer: loss of natural immune surveillance as the correct ‘target’ for therapy! seeing the ‘Elephant’ in the light of logic. Cell Biochem Biophys 2012, 62:501-509.