IMPLICATIONS OF GHRELIN AXIS IN BREAST CANCER - REVIEW
Abstract
Breast cancer is, by far, the most frequent cancer among women and many factors influence the physiological and pathological growth and development of the mammary gland. There is developing evidence that the hormone ghrelin, known for the growth hormone releasing effect and food intake modulator, could also play a role in the pathogenesis of breast cancer and may represent a new diagnostic marker and a potential therapeutic target. We performed a PubMed Database search of relevant studies and ten papers were included in our systematic review. Ghrelin axis seems to be definitely involved in the pathogenesis of breast cancer, although a precise role has not been yet established. In order to verify the precise role of ghrelin axis in breast cancer further studies with larger populations are necessary that should include the analysis of metabolic, genetic and environmental factors which are expected to influence the results.
References
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2. Cancer Research UK [Internet]. UK: Breast Cancer Risk Factors; c2013 [updated 2014 May 21; cited 2015 Jan 5]. Available from: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/ breast/riskfactors/breast-cancer-risk-factors#Breast .
3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth hormone releasing acylated peptide from stomach. Nature 1999; 402: 656-660.
4. Kojima M, Hosoda H, Kangawa K. Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Hormone Res 2001; 56(1): 93-97.
5. Howard AD, Feighner SD, Cullyetal DF. Areceptorin pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273(5277): 974-977.
6. Patterson M. Murphy KG, le Roux CW, Ghatei MA, Bloom SR. Characterization of ghrelin-like immunoreactivity in human plasma, J Clin Endocrinol Metab 2005; 90(4): 2205-2211.
7. Kojima M, Kanganawa K. Ghrelin: structure and function. Phisiol Rev 2005; 85: 495-522.
8. Takahashi T, Ida T, Sato T, Nakashima Y, Nakamura Y, Tsuji A, Kojima M. Production of n-octanoyl-modified ghrelin in cultured cells requires prohormone processing protease and ghrelin O-acyltransferase, as well as n-octanoic acid. J Biochem 2009; 146: 675-682.
9. Zhu X, Cao Y, Voogd K, Steiner DF. On the processing of proghrelin to ghrelin. J Biol Chem 2006; 281: 38867-38870.
10. Zhang JV, Ren PG, Avsian-Kretchmer O et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 2005; 310: 996-999.
11. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008; 132: 387-396.
12. Gutierrez JA, Solenberg PJ, Perkins DR et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 2008; 105: 6320-6325.
13. Satou M, Nishi Y, Yoh J, Hattori Y, Sugimoto H. Identification and characterization of acyl-protein thioes- terase 1/lysophospholipase I as a ghrelin deacylation/lyso- phospholipid hydrolyzing enzyme in fetal bovine serum and conditioned medium. Endocrinol 2010; 151: 4765-4775.
14. Yoh J, Nishi Y, Hosoda H et al. Plasma levels of n-decanoyl ghrelin, an- other acyl- and active-form of ghrelin, in human subjects and the effect of glucose- or meal-ingestion on its dynamics. Regul Pept 2011; 167: 140-148.
15. McKee KK, Palyha OC, Feighner SD et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415-423.
16. Howard AD, Feighner SD, Cully DF et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-977.
17. Hosoda H, Kojima M, Matsuo H, Kanganawa K. Purification and characterization of rat des-Gln14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000; 275: 1995-2000.
18. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Strutural divergence of human ghrelin-derived molecules produced by post-translational processing. J Biol Chem 2003; 278: 64-70.
19. Jeffery PL, Duncan RP, Yeh AH et al. Expression of the ghrelin axis in the mouse; an exon 4-deleted mouse proghrelin variant encodes a novel C terminal peptide. Endocrinol 2005; 146: 432-440.
20. Yeh AH, Jeffery PL, Duncan RP, Herington AC. Chopin LK. Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer. Clin Cancer Res 2005; 11: 8295-8303.
21. Takaya K, Ariyasu H, Kanamoto N et al. Ghrelin strongly stimulates growth hormone (GH) release in humans. J Clin Endocrinol Metab 2000; 85(12): 4908- 4911.
22. Hataya Y, Akamizu T, Takaya K et al. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001; 86(9): 4552-4555.
23. Correa-Silva SR, Nascif SO, Lengyel AMJ. Decreased GH secretion and enhanced ACTH and corti-sol release after ghrelin administration in Cushing’s disease: comparison with GH-releasing peptide-6 (GHRP-6) and GHRH. Pituitary 2006; 9(2): 101-107.
24. Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annual Review of Medicine 2003; 54:453-471. Tschop M, Wawarta R, Riepl RL et al. Post-prandial decrease of circu-lating human ghrelin levels. J Endocrinol Invest 2001; 24(6): RC19-RC21.
25. De Vriese C, Perret J, Delporte C. Current and future clinical applications of ghrelin. Endocrine Disease, IConcept Press Ltd 2013 http://dx.doi.org/10.1155/2013/518909 .
26. Docato MM, Yang F, Callaghan B, Au CC, Ragavan R, Wang X, Furness JB, Andrews ZB, Brown KA. Ghrelin and des-acyl ghrelin inhibit aromatase expression and activity in human adipose stromal cells: suppression of cAMP as a possible mechanism. Breast Cancer Res Treat 2014; 147(1): 193-201.
27. Barazzoni R, Zanetti M, Ferreira C et al. Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. J Clin Endocrinol Metab 2007; 92(10): 3935-3940.
28. Fernandez-Fernandez R, Martini AC, Navarro VM et al. Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol 2006; 254-255: 127-132.
29. Fernandez-Fernandez R, Tena-Sempere M, Aguilar E, Pinilla L. Ghrelin effects on gonadotropin secretion in male and female rats. Neuroscience Letters 2004; 362(2): 103-107.
30. Lebrethon MC, Aganina A, Fournier M, Gerard E, Parent AS, Bourguignon JP. Effects of in vivo and in vitro administration of ghrelin, leptin and neuropeptide mediators on pulsatile gonadotrophin-releasing hormone secretion from male rat hypothalamus before and after puberty. J Neuroendocrinol 2007; 19(3): 181-188.
31. Chopin LK, Seim I, Walpole CM, Herington AC. The ghrelin axis - Does it have an appetite for cancer progression? Endocrine Reviews 2012; 33(6): 849-891.
32. Stefanaki C, Rorris FP, Stamatakos M. The Role of Ghrelin Signals in Breast Cancer- A Systematic Review. Curr Signal Transduct Ther 2012; 7(3): 247-253.
33. Cassoni P, Papotti M, Ghè C et al. Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab 2001; 86: 1738-1745.
34. Jeffery PL, Murray RE, Yeh AH et al. Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and celllines. Endocrine-Related Cancer 2005; 12: 839-850.
35. Wagner K, Hemminki K, Grzybowska E et al. Polymorphisms in genes involved in GH1 release and their association with breast cancer risk. Carcinogenesis 2006; 9: 1867-1875.
36. Dossus L, McKay JD, Canzian F et al. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Carcinogenesis 2008; 29(7): 1360-1366.
37. Feigelson HS, Teras LR, Diver WR, et al. Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Preven-tion Study II. Breast Cancer Res 2008; 10(4): R57.
38. Ordway JM, Budiman MA, Korshunova Y et al. Identification of novel high-frequency DNA meth-ylation changes in breast cancer. PLoS One 2007; 2(12): e131438.
39. Gahete MD, Córdoba-Chacón J, Hergueta-Redondo M et al. A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance. PLoS One 2011; 6(8): e23302.
40. Grönberg M, Fjällskog ML, Jirström K, Janson ET. Expression of ghrelin is correlated to a favorable outcome in invasive breast cancer. Acta Oncol 2011; 51(3): 386-393.
41. Botla SK, Gholami AM, Malekpour M et al. Diagnostic values of GHSR DNA methylation pattern in breastcancer. Breast Cancer Res Treat 2012; 135: 705-713.
2. Cancer Research UK [Internet]. UK: Breast Cancer Risk Factors; c2013 [updated 2014 May 21; cited 2015 Jan 5]. Available from: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/ breast/riskfactors/breast-cancer-risk-factors#Breast .
3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth hormone releasing acylated peptide from stomach. Nature 1999; 402: 656-660.
4. Kojima M, Hosoda H, Kangawa K. Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Hormone Res 2001; 56(1): 93-97.
5. Howard AD, Feighner SD, Cullyetal DF. Areceptorin pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273(5277): 974-977.
6. Patterson M. Murphy KG, le Roux CW, Ghatei MA, Bloom SR. Characterization of ghrelin-like immunoreactivity in human plasma, J Clin Endocrinol Metab 2005; 90(4): 2205-2211.
7. Kojima M, Kanganawa K. Ghrelin: structure and function. Phisiol Rev 2005; 85: 495-522.
8. Takahashi T, Ida T, Sato T, Nakashima Y, Nakamura Y, Tsuji A, Kojima M. Production of n-octanoyl-modified ghrelin in cultured cells requires prohormone processing protease and ghrelin O-acyltransferase, as well as n-octanoic acid. J Biochem 2009; 146: 675-682.
9. Zhu X, Cao Y, Voogd K, Steiner DF. On the processing of proghrelin to ghrelin. J Biol Chem 2006; 281: 38867-38870.
10. Zhang JV, Ren PG, Avsian-Kretchmer O et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 2005; 310: 996-999.
11. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008; 132: 387-396.
12. Gutierrez JA, Solenberg PJ, Perkins DR et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 2008; 105: 6320-6325.
13. Satou M, Nishi Y, Yoh J, Hattori Y, Sugimoto H. Identification and characterization of acyl-protein thioes- terase 1/lysophospholipase I as a ghrelin deacylation/lyso- phospholipid hydrolyzing enzyme in fetal bovine serum and conditioned medium. Endocrinol 2010; 151: 4765-4775.
14. Yoh J, Nishi Y, Hosoda H et al. Plasma levels of n-decanoyl ghrelin, an- other acyl- and active-form of ghrelin, in human subjects and the effect of glucose- or meal-ingestion on its dynamics. Regul Pept 2011; 167: 140-148.
15. McKee KK, Palyha OC, Feighner SD et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415-423.
16. Howard AD, Feighner SD, Cully DF et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-977.
17. Hosoda H, Kojima M, Matsuo H, Kanganawa K. Purification and characterization of rat des-Gln14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000; 275: 1995-2000.
18. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K. Strutural divergence of human ghrelin-derived molecules produced by post-translational processing. J Biol Chem 2003; 278: 64-70.
19. Jeffery PL, Duncan RP, Yeh AH et al. Expression of the ghrelin axis in the mouse; an exon 4-deleted mouse proghrelin variant encodes a novel C terminal peptide. Endocrinol 2005; 146: 432-440.
20. Yeh AH, Jeffery PL, Duncan RP, Herington AC. Chopin LK. Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer. Clin Cancer Res 2005; 11: 8295-8303.
21. Takaya K, Ariyasu H, Kanamoto N et al. Ghrelin strongly stimulates growth hormone (GH) release in humans. J Clin Endocrinol Metab 2000; 85(12): 4908- 4911.
22. Hataya Y, Akamizu T, Takaya K et al. A low dose of ghrelin stimulates growth hormone (GH) release synergistically with GH-releasing hormone in humans. J Clin Endocrinol Metab 2001; 86(9): 4552-4555.
23. Correa-Silva SR, Nascif SO, Lengyel AMJ. Decreased GH secretion and enhanced ACTH and corti-sol release after ghrelin administration in Cushing’s disease: comparison with GH-releasing peptide-6 (GHRP-6) and GHRH. Pituitary 2006; 9(2): 101-107.
24. Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annual Review of Medicine 2003; 54:453-471. Tschop M, Wawarta R, Riepl RL et al. Post-prandial decrease of circu-lating human ghrelin levels. J Endocrinol Invest 2001; 24(6): RC19-RC21.
25. De Vriese C, Perret J, Delporte C. Current and future clinical applications of ghrelin. Endocrine Disease, IConcept Press Ltd 2013 http://dx.doi.org/10.1155/2013/518909 .
26. Docato MM, Yang F, Callaghan B, Au CC, Ragavan R, Wang X, Furness JB, Andrews ZB, Brown KA. Ghrelin and des-acyl ghrelin inhibit aromatase expression and activity in human adipose stromal cells: suppression of cAMP as a possible mechanism. Breast Cancer Res Treat 2014; 147(1): 193-201.
27. Barazzoni R, Zanetti M, Ferreira C et al. Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. J Clin Endocrinol Metab 2007; 92(10): 3935-3940.
28. Fernandez-Fernandez R, Martini AC, Navarro VM et al. Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol 2006; 254-255: 127-132.
29. Fernandez-Fernandez R, Tena-Sempere M, Aguilar E, Pinilla L. Ghrelin effects on gonadotropin secretion in male and female rats. Neuroscience Letters 2004; 362(2): 103-107.
30. Lebrethon MC, Aganina A, Fournier M, Gerard E, Parent AS, Bourguignon JP. Effects of in vivo and in vitro administration of ghrelin, leptin and neuropeptide mediators on pulsatile gonadotrophin-releasing hormone secretion from male rat hypothalamus before and after puberty. J Neuroendocrinol 2007; 19(3): 181-188.
31. Chopin LK, Seim I, Walpole CM, Herington AC. The ghrelin axis - Does it have an appetite for cancer progression? Endocrine Reviews 2012; 33(6): 849-891.
32. Stefanaki C, Rorris FP, Stamatakos M. The Role of Ghrelin Signals in Breast Cancer- A Systematic Review. Curr Signal Transduct Ther 2012; 7(3): 247-253.
33. Cassoni P, Papotti M, Ghè C et al. Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab 2001; 86: 1738-1745.
34. Jeffery PL, Murray RE, Yeh AH et al. Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and celllines. Endocrine-Related Cancer 2005; 12: 839-850.
35. Wagner K, Hemminki K, Grzybowska E et al. Polymorphisms in genes involved in GH1 release and their association with breast cancer risk. Carcinogenesis 2006; 9: 1867-1875.
36. Dossus L, McKay JD, Canzian F et al. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Carcinogenesis 2008; 29(7): 1360-1366.
37. Feigelson HS, Teras LR, Diver WR, et al. Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Preven-tion Study II. Breast Cancer Res 2008; 10(4): R57.
38. Ordway JM, Budiman MA, Korshunova Y et al. Identification of novel high-frequency DNA meth-ylation changes in breast cancer. PLoS One 2007; 2(12): e131438.
39. Gahete MD, Córdoba-Chacón J, Hergueta-Redondo M et al. A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance. PLoS One 2011; 6(8): e23302.
40. Grönberg M, Fjällskog ML, Jirström K, Janson ET. Expression of ghrelin is correlated to a favorable outcome in invasive breast cancer. Acta Oncol 2011; 51(3): 386-393.
41. Botla SK, Gholami AM, Malekpour M et al. Diagnostic values of GHSR DNA methylation pattern in breastcancer. Breast Cancer Res Treat 2012; 135: 705-713.
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