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Journal of Cancer Research and Treatment. 2016, 4(5), 80-87
DOI: 10.12691/jcrt-4-5-2
Open AccessReview Article

Tumor Markers of Breast Cancer: Role in Early Diagnosis, Monitoring Response to Therapy and Determination of Prognosis

Ahmed M. Kabel1, 2, , Aisha H. Al-shehri3, Batool S. Madani3, Sheemah I. Al-shafie3 and Shroog A. Amasha3

1Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, KSA

2Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt

3Final year student, College of Pharmacy, Taif University, Taif, KSA

Pub. Date: September 27, 2016

Cite this paper:
Ahmed M. Kabel, Aisha H. Al-shehri, Batool S. Madani, Sheemah I. Al-shafie and Shroog A. Amasha. Tumor Markers of Breast Cancer: Role in Early Diagnosis, Monitoring Response to Therapy and Determination of Prognosis. Journal of Cancer Research and Treatment. 2016; 4(5):80-87. doi: 10.12691/jcrt-4-5-2


A tumor marker is a substance that is produced by the body in response to malignant tumors, or produced by the cancer itself. Some of these markers are specific to one cancer, while others are seen in several types of cancer. These markers are generally used to evaluate the patient's response to treatment or to monitor the presence of metastasis or recurrence. Breast cancer is one of the most common malignancies in females worldwide. Tumor markers may play a role in early detection, and hence favourable prognosis of breast cancer. The CA 27-29 is a tumor marker that is most often used in people with breast cancer. Also, CA 15-3, BR 27.29 (CA27.29), carcinoembryonic antigen (CEA), tissue polypeptide specific antigen, p53, cathepsin D, cyclin E, nestin and HER-2 are widely used for diagnosis, monitoring response to therapy, early detection of metastasis and determination of recurrence of breast cancer.

tumor markers breast cancer prognosis

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[1]  Sharma S. Tumor markers in clinical practice: General principles and guidelines. Indian Journal of Medical and Paediatric Oncology: Official Journal of Indian Society of Medical & Paediatric Oncology 2009; 30(1):1-8.
[2]  Duffy M.J. Tumor Markers in Clinical Practice: A Review Focusing on Common Solid Cancers. Med Princ Pract 2013; 22: 4-11.
[3]  Amayo AA, Kuria JG. Clinical application of tumour markers: a review. East Afr Med J 2009; 86(12 Suppl):S76-83.
[4]  Kabel AM, Baali FH. Breast Cancer: Insights into Risk Factors, Pathogenesis, Diagnosis and Management. Journal of Cancer Research and Treatment 2015; 3(2): 28-33.
[5]  Mohammadbeigi A, Mohammadsalehi N, Valizadeh R, Momtaheni Z, Mokhtari M, Ansari H. Lifetime and 5 years risk of breast cancer and attributable risk factor according to Gail model in Iranian women. Journal of Pharmacy & Bioallied Sciences 2015; 7(3):207-11.
[6]  Shah R, Rosso K, Nathanson SD. Pathogenesis, prevention, diagnosis and treatment of breast cancer. World Journal of Clinical Oncology 2014; 5(3):283-98.
[7]  Banegas MP, Bird Y, Moraros J, King S, Prapsiri S, Thompson B. Breast Cancer Knowledge, Attitudes, and Early Detection Practices in United States-Mexico Border Latinas. Journal of Women’s Health 2012; 21(1):101-7.
[8]  Marić P, Ozretić P, Levanat S, Oresković S, Antunac K, Beketić-Oresković L. Tumor markers in breast cancer--evaluation of their clinical usefulness. Coll Antropol 2011; 35(1):241-7.
[9]  Donepudi MS, Kondapalli K, Amos SJ, Venkanteshan P. Breast cancer statistics and markers. J Cancer Res Ther 2014; 10(3):506-11.
[10]  Shao Y, Sun X, He Y, Liu C, Liu H. Elevated Levels of Serum Tumor Markers CEA and CA15-3 Are Prognostic Parameters for Different Molecular Subtypes of Breast Cancer. Batra SK, ed. PLoS ONE 2015; 10(7):e0133830.
[11]  Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer 2012; 76(2):138-43.
[12]  Hammarström S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues*1. Seminars in Cancer Biology 1999; 9(2): 67-81.
[13]  Klaile E, Klassert TE, Scheffrahn I, et al. Carcinoembryonic antigen (CEA)-related cell adhesion molecules are co-expressed in the human lung and their expression can be modulated in bronchial epithelial cells by non-typable Haemophilus influenzae, Moraxella catarrhalis, TLR3, and type I and II interferons. Respiratory Research 2013; 14(1):85.
[14]  Guadagni F, Ferroni P, Carlini S, Mariotti S, Spila A, Aloe S, et al. A re-evaluation of carcinoembryonic antigen (CEA) as a serum marker for breast cancer: a prospective longitudinal study. Clin Cancer Res 2001; 7(8):2357-62.
[15]  Wu SG, He ZY, Zhou J, Sun JY, Li FY, Lin Q, et al. Serum levels of CEA and CA15-3 in different molecular subtypes and prognostic value in Chinese breast cancer. Breast 2014; 23(1): 88-93.
[16]  Park BW, Oh JW, Kim JH, Park SH, Kim KS, Kim JH,et al. Preoperative CA 15-3 and CEA serum levels as predictor for breast cancer outcomes. Ann Oncol 2008;19(4):675-81.
[17]  Manuali E, De Giuseppe A, Feliziani F, et al. CA 15–3 cell lines and tissue expression in canine mammary cancer and the correlation between serum levels and tumour histological grade. BMC Veterinary Research 2012; 8:86.
[18]  David JM, Hamilton DH, Palena C. MUC1 upregulation promotes immune resistance in tumor cells undergoing brachyury-mediated epithelial-mesenchymal transition. Oncoimmunology 2016; 5(4): e1117738.
[19]  Bahrami-Ahmadi A, Makarian F, Mortazavizadeh MR, Yazdi MF, Chamani M. Symptomatic metastasis prediction with serial measurements of CA 15.3 in primary breast cancer patients. Journal of Research in Medical Sciences 2012; 17(9):850-4.
[20]  Rack B, Schindlbeck C, Jückstock J, Genss EM, Hepp P, Lorenz R, et al. Prevalence of CA 27.29 in primary breast cancer patients before the start of systemic treatment. Anticancer Res 2010; 30(5):1837-41.
[21]  Vaidyanathan K, Vasudevan DM. Organ Specific Tumor Markers: What’s New? Indian Journal of Clinical Biochemistry 2012; 27(2):110-20.
[22]  Graham LJ, Shupe MP, Schneble EJ, et al. Current Approaches and Challenges in Monitoring Treatment Responses in Breast Cancer. Journal of Cancer 2014; 5(1):58-68.
[23]  Hou MF, Chen YL, Tseng TF, Lin CM, Chen MS, Huang CJ, et al. Evaluation of serum CA27.29, CA15-3 and CEA in patients with breast cancer. Kaohsiung J Med Sci 1999; 15(9): 520-8.
[24]  Kabel AM, El-Rashidy MA, Omar MS. Ameliorative Potential of Tamoxifen/Thymoquinone Combination in Patients with Breast Cancer: A Biochemical and Immunohistochemical Study. Cancer Med Anticancer Drug 2016; 1:102.
[25]  Zwart W, Theodorou V, Carroll JS. Estrogen receptor-positive breast cancer: a multidisciplinary challenge. Wiley Interdiscip Rev Syst Biol Med 2011; 3(2):216-30.
[26]  Kumar R, Zakharov MN, Khan SH, et al. The Dynamic Structure of the Estrogen Receptor. Journal of Amino Acids2011; 2011: Article ID 812540.
[27]  Lumachi F, Brunello A, Maruzzo M, Basso U, Basso SM. Treatment of estrogen receptor-positive breast cancer. Curr Med Chem 2013; 20(5): 596-604.
[28]  Bae SY, Kim S, Lee JH, et al. Poor prognosis of single hormone receptor- positive breast cancer: similar outcome as triple-negative breast cancer. BMC Cancer 2015; 15:138.
[29]  Chan M, Chang MC, González R, , Lategan B, del Barco E, Vera-Badillo F, et al. Outcomes of Estrogen Receptor Negative and Progesterone Receptor Positive Breast Cancer. PLoS ONE 2015; 10(7): e0132449.
[30]  Groenendijk FH, Zwart W, Floore A, Akbari S, Bernards R. Estrogen receptor splice variants as a potential source of false-positive estrogen receptor status in breast cancer diagnostics. Breast Cancer Research and Treatment 2013;140(3):475-484.
[31]  Jacobsen BM, Horwitz KB. Progesterone Receptors, their Isoforms and Progesterone Regulated Transcription. Molecular and Cellular Endocrinology 2012; 357(1-2):18-29.
[32]  Mc Cormack O, Harrison M, Kerin MJ, McCann A. Role of the progesterone receptor (PR) and the PR isoforms in breast cancer. Crit Rev Oncog 2007; 13(4):283-301.
[33]  Giulianelli S, Molinolo A, Lanari C.Targeting progesterone receptors in breast cancer. Vitam Horm 2013; 93:161-84.
[34]  Lanari C, Wargon V, Rojas P, Molinolo AA. Antiprogestins in breast cancer treatment: are we ready? Endocr Relat Cancer 2012; 19(3): R35-50.
[35]  Yang L-H, Tseng H-S, Lin C, et al. Survival Benefit of Tamoxifen in Estrogen Receptor-Negative and Progesterone Receptor-Positive Low Grade Breast Cancer Patients. Journal of Breast Cancer 2012;15(3):288-95.
[36]  Krishnamurti U, Silverman JF. HER2 in breast cancer: a review and update. Adv Anat Pathol 2014; 21(2):100-7.
[37]  Gutierrez C, Schiff R. HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 2011; 135(1):55-62.
[38]  English DP, Roque DM, Santin AD. HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies. Molecular diagnosis & therapy 2013; 17(2):85-99.
[39]  Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu Rev Med 2015; 66:111-28.
[40]  Savci-Heijink CD, Halfwerk H, Hooijer GKJ, Horlings HM, Wesseling J, van de Vijver MJ. Retrospective analysis of metastatic behaviour of breast cancer subtypes. Breast Cancer Research and Treatment 2015; 150(3): 547-57.
[41]  Dawson SJ, Provenzano E, Caldas C. Triple negative breast cancers: clinical and prognostic implications. Eur J Cancer 2009; 45(1): 27-40.
[42]  Creighton CJ, Massarweh S, Huang S, Tsimelzon A, Hilsenbeck SG, Osborne CK, et al. Development of resistance to targeted therapies transforms the clinically associated molecular profile subtype of breast tumor xenografts. Cancer Res 2008; 68: 7493-501.
[43]  Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, et al. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst 2007; 99:694-705.
[44]  Johnston SR. New strategies in estrogen receptor-positive breast cancer. Clin Cancer Res 2010; 16:1979-87.
[45]  Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al. Mechanisms of tamoxifen resistance:increased estrogen receptor-HER2/neu crosstalk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004; 96: 926-35.
[46]  Chang M. Tamoxifen Resistance in Breast Cancer. Biomolecules & Therapeutics. 2012; 20(3): 256-67.
[47]  Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 2003; 95:353-61.
[48]  Holloway JN, Murthy S, El-Ashry D. A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-alpha down-regulation in breast cancer cells: the role of nuclear factor-kappaB. Mol Endocrinol 2004; 18:1396-410.
[49]  Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, et al. Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 2006; 8:R4.
[50]  García-Becerra R, Santos N, Díaz L, Camacho J. Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance. International Journal of Molecular Sciences 2013; 14(1):108-45.
[51]  Stillfried GE, Saunders DN, Ranson M. Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res 2007; 9(1):R14.
[52]  Tang L, Han X. The urokinase plasminogen activator system in breast cancer invasion and metastasis. Biomed Pharmacother 2013; 67(2): 179-82.
[53]  Moirangthem A, Bondhopadhyay B, Mukherjee M, et al. Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Scientific Reports 2016; 6:21903.
[54]  Ma Z, Webb DJ, Jo M, Gonias SL. Endogenously produced urokinase-type plasminogen activator is a major determinant of the basal level of activated ERK/MAP kinase and prevents apoptosis in MDA-MB-231 breast cancer cells. Journal of Cell Science 2001; 114: 3387-96.
[55]  Lampelj M, Arko D, Cas-Sikosek N, et al. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) in breast cancer - correlation with traditional prognostic factors. Radiology and Oncology 2015; 49(4):357-64.
[56]  Kim EY, Do S-I, Hyun K, et al. High Expression of Urokinase-Type Plasminogen Activator Is Associated with Lymph Node Metastasis of Invasive Ductal Carcinoma of the Breast. Journal of Breast Cancer 2016; 19(2):156-62.
[57]  Kabel AM. Tumor protein p53: Novel aspects of an old tumor marker. Journal of Cancer Research and Treatment 2015; 3(2): 25-7.
[58]  Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Levine AJ, ed. Genes & Cancer 2011;2(4):466-74.
[59]  Li DH, Zhang LQ, He FC. Advances on mutant p53 research. Yi Chuan 2008; 30(6): 697-703.
[60]  Parrales A, Iwakuma T. Targeting Oncogenic Mutant p53 for Cancer Therapy. Frontiers in Oncology 2015; 5:288.
[61]  Zargaran M, Moghimbeigi A, Afsharmoghadam N, Nasr Isfahani M, Hashemi A. A Comparative Study of Cathepsin D Expression in Peripheral and Central Giant Cell Granuloma of the Jaws by Immunohistochemistry Technique. Journal of Dentistry 2016; 17(2): 98-104.
[62]  Masson O, Prébois C, Derocq D, Meulle A, Dray C, Daviaud D, et al. Cathepsin-D, a Key Protease in Breast Cancer, Is Up-Regulated in Obese Mouse and Human Adipose Tissue, and Controls Adipogenesis. PLoS ONE 2011; 6(2): e16452.
[63]  Vetvicka V, Fusek M, Vashishta A. Procathepsin D Involvement in Chemoresistance of Cancer Cells. North American Journal of Medical Sciences 2012; 4(4): 174-9.
[64]  Vetvicka V, Fusek M. Procathepsin D as a tumor marker, anti-cancer drug or screening agent. Anticancer Agents Med Chem 2012; 12(2): 172-5.
[65]  Huang XF, Wang CM, Dai XW, et al. Expressions of chromogranin A and cathepsin D in human primary hepatocellular carcinoma. World Journal of Gastroenterology 2000; 6(5):693-8.
[66]  Trovesi C, Manfrini N, Falcettoni M, Longhese MP. Regulation of the DNA damage response by cyclin-dependent kinases. J Mol Biol 2013; 425(23):4756-66.
[67]  Bi H, Li S, Qu X, et al. DEC1 regulates breast cancer cell proliferation by stabilizing cyclin E protein and delays the progression of cell cycle S phase.Cell Death & Disease 2015; 6(9):e1891.
[68]  Akli S, Bui T, Wingate H, et al. Low molecular weight (LMW) cyclin E can bypass letrozole-induced G1 arrest in human breast cancer cells and tumors. Clinical cancer research: an official journal of the American Association for Cancer Research 2010; 16(4):1179.
[69]  Zhong B, Wang T, Zou J, et al. Association of the intermediate filament nestin with cancer stage: a meta-analysis based on 223 positive/high nestin cases and 460 negative/low case-free controls. Oncotarget 2015; 6(26):22970-7.
[70]  Neradil J, Veselska R. Nestin as a marker of cancer stem cells. Cancer Science 2015; 106(7): 803-11.
[71]  Choo JR, Nielsen TO. Biomarkers for Basal-like Breast Cancer. Cancers 2010; 2(2):1040-65.
[72]  Richter A, Nissen N, Mailänder P, et al. Mammary gland-derived nestin-positive cell populations can be isolated from human male and female donors. Stem Cell Research & Therapy 2013; 4(4):78.
[73]  Liu C, Chen B, Zhu J, Zhang R, Yao F, Jin F, et al. Clinical implications for nestin protein expression in breast cancer. Cancer Sci 2010; 101(3):815-9.