JOURNAL of
ONCOLOGICAL
SCIENCES

REVIEW ARTICLE

Breast cancer genetic susceptibility: With focus in Saudi Arabia
Received Date : 22 Dec 2018
Accepted Date : 05 Feb 2019
Doi: 10.1016/j.jons.2019.02.001 - Article's Language: EN
J Oncol Sci 5 (2019) 6-12
This is an open access article under the CC BY-NC-ND license
ABSTRACT
In recent years there have been important advances in molecular genetics and linkage analysis of the breast cancer. Beside germline BRCA1 or BRAC2 mutations, and somatic genetic alterations, epigenetic alterations in numerous genes play an essential role in the tumorigenesis of breast cancer. TP53, STK11, PTEN, CDH1, NF1 or NBN mutations are associated with high breast cancer associated syndromes. Mutations in DNA repair associated genes (ATM, CHEK2, BRIP1, PALB2 and RAD50) are associated with increased breast cancer risk. Moreover, several single nucleotide polymorphisms (SNPs) were considered as breast cancer susceptibility polymorphisms within genes (FGFR2, TOX3, LSP1, MAP3K1, and TGFB1). This review discusses breast cancer genetic susceptibility, highlights recent advances in breast cancer genetics, with a particular focus in Saudi women.
KAYNAKLAR
  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA Oncol. 2017 Apr 1;3(4):524e548. https://doi.org/10.1001/ jamaoncol.2016.5688.
  2. Chollet-Hinton L, Anders CK, Tse C-K, et al. Breast cancer biologic and etiologic heterogeneity by young age and menopausal status in the Carolina Breast Cancer Study: a case-control study. Breast Cancer Res. 2016;18:79. https:// doi.org/10.1186/s13058-016-0736-y. [Crossref]  [PubMed]  [PMC] 
  3. Turkoz FP, Solak M, Petekkaya I, et al. Association between common risk factors and molecular subtypes in breast cancer patients. Breast. 2013 Jun;22(3):344e350. https://doi.org/10.1016/j.breast.2012.08.005. [Crossref]  [PubMed] 
  4. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014;32(19):2001e2009. [Crossref]  [PubMed]  [PMC] 
  5. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol. 2015;26(7):1291e1299. https://doi.org/10.1093/annonc/mdv022. [Crossref]  [PubMed]  [PMC] 
  6. Meads C, Ahmed I, Riley RD. A systematic review of breast cancer incidence risk prediction models with meta-analysis of their performance. Breast Canc Res Treat. 2012;132:365e377. https://doi.org/10.1007/s10549-011-1818-2. [Crossref]  [PubMed] 
  7. Semlali A, Almutairi M, Parine NR, et al. No genetic relationship between TLR2 rs4696480, rs3804100, and rs3804099 gene polymorphisms and female breast cancer in Saudi populations. OncoTargets Ther. 2017;10:2325e2333. https://doi.org/10.2147/OTT.S121618. [Crossref]  [PubMed]  [PMC] 
  8. Walker LC, Waddell N, Ten Haaf A, Investigators kConFab, Grimmond S, Spurdle AB. Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers. Breast Canc Res Treat. 2008 Nov;112(2):229e236. [Crossref]  [PubMed] 
  9. Bradbury AR, Olopade OI. Genetic susceptibility to breast cancer. Rev Endocr Metab Disord. 2007;8:255e267. [Crossref]  [PubMed] 
  10. Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med. 2003;348: 2339e2347. [Crossref]  [PubMed] 
  11. Nathanson KL, Wooster R, Weber BL. Breast cancer genetics: what we know and what we need. Nat Med. 2001;7:552e556. [Crossref]  [PubMed] 
  12. Meindl A. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002;97:472e480, 6. [Crossref]  [PubMed] 
  13. Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genom Hum Genet. 2008;9:321e345. [Crossref]  [PubMed] 
  14. Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250:1684e1689. [Crossref]  [PubMed] 
  15. Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12e13. Science. 1994;265: 2088e2090. [Crossref]  [PubMed] 
  16. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26:2568e2581. [Crossref]  [PubMed] 
  17. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. The pathology offamilial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20:2310e2318. [Crossref]  [PubMed] 
  18. Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet. 2008;40:17e22. [Crossref]  [PubMed] 
  19. King MC, Marks JH, Mandell JB, New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643e646. [Crossref]  [PubMed] 
  20. Lindor NM, McMaster ML, Lindor CJ, et al. Concise handbook of familial cancer susceptibility syndromesdsecond edition. J Natl Cancer Inst Monogr. 2008;1e93. [Crossref]  [PubMed] 
  21. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22: 735e742. [Crossref]  [PubMed] 
  22. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Am Med Assoc. 2017;317(23):2402e2416. https://doi.org/10.1001/jama.2017.7112. [Crossref]  [PubMed]  [PMC] 
  23. Merdad A, Gari MA, Hussein S, et al. Characterization of familial breast cancer in Saudi Arabia. BMC Genomics. 2015;16(suppl 1):S3. https://doi.org/10.1186/ 1471-2164-16-S1-S3. [Crossref]  [PubMed]  [PMC] 
  24. Alhuqail AJ, Alzahrani A, Almubarak H, et al. High prevalence of deleterious BRCA1 and BRCA2 germline mutations in arab breast and ovarian cancer patients. Breast Canc Res Treat. 2018 Apr;168(3):695e702. https://doi.org/ 10.1007/s10549-017-4635-4. [Crossref]  [PubMed] 
  25. Calhoun BC, Collins LC. Predictive markers in breast cancer: an update on ER and HER2 testing and reporting. Semin Diagn Pathol. 2015 Sep;32(5): 362e369. https://doi.org/10.1053/j.semdp.2015.02.011. [Crossref]  [PubMed] 
  26. Myburgh EJ, Langenhoven L, Grant KA, van der Merwe L, Kotze MJ. Clinical overestimation of HER2 positivity in early estrogen and progesterone receptorepositive breast cancer and the value of molecular subtyping using BluePrint. J Glob Oncol. 2017;3(4):314e322. https://doi.org/10.1200/ JGO.2016.006072. [Crossref]  [PubMed]  [PMC] 
  27. Lim E, Tarulli G, Portman N, Hickey TE, Tilley WD, Palmieri C. Pushing estrogen receptor around in breast cancer. Endocr Relat Cancer. 2016 Dec;23(12):T227eT241. [Crossref]  [PubMed] 
  28. Schettini F, Buono G, Cardalesi C, Desideri I, De Placido S, Del Mastro L. Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: where we are now and where we are going. Cancer Treat Rev. 2016 May;46:20e26. https://doi.org/10.1016/j.ctrv.2016.03.012. [Crossref]  [PubMed] 
  29. Sunami E, Shinozaki M, Sim M-S, et al. Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res. 2008;10(3):R46. https://doi.org/10.1186/bcr2098. [Crossref]  [PubMed]  [PMC] 
  30. Bae YK, Brown A, Garrett E, et al. Hypermethylation in histologically distinct classes of breast cancer. Clin Cancer Res. 2004;10:5998e6005. https://doi.org/ 10.1158/1078-0432.CCR-04-0667. [Crossref]  [PubMed]  [PMC] 
  31. Issa JP. DNA methylation as a therapeutic target in cancer. Clin Cancer Res. 2007;13:1634e1637. https://doi.org/10.1158/1078-0432.CCR-06-2076. [Crossref]  [PubMed] 
  32. Widschwendter M, Siegmund KD, Muller HM, et al. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res. 2004;64:3807e3813. https://doi.org/10.1158/0008- 5472.CAN-03-3852. [Crossref]  [PubMed] 
  33. El-Harith el-HA, Abdel-Hadi MS, Steinmann D, Dork T. BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia. Saudi Med J. 2002 Jun;23(6):700e704.
  34. Hasan TN, Shafi G, Syed NA, Alsaif MA, Alsaif AA, Alshatwi AA. Lack of association of BRCA1 and BRCA2 variants with breast cancer in an ethnic population of Saudi Arabia, an emerging high-risk area. Asian Pac J Cancer Prev. 2013;14(10):5671e5674. [Crossref]  [PubMed] 
  35. Merdad A, Gari MA, Hussein S, et al. Characterization of familial breast cancer in Saudi Arabia. BMC Genomics. 2015;16(suppl 1):S3. https://doi.org/10.1186/ 1471-2164-16-S1-S3. [Crossref]  [PubMed]  [PMC] 
  36. Amemiya Y, Bacopulos S, Al-Shawarby M. A comparative analysis of breast and ovarian cancer-related gene mutations in Canadian and Saudi arabian patients with breast cancer. Anticancer Res. 2015 May;35(5):2601e2610.
  37. Khabaz MN. Immunohistochemistry subtypes (ER/PR/HER) of breast cancer: where do we stand in the West of Saudi Arabia? Asian Pac J Cancer Prev. 2014;15(19):8395e8400. [Crossref]  [PubMed] 
  38. Alnegheimish NA, Alshatwi RA, Alhefdhi RM, Arafah MM, AlRikabi AC, Husain S. Molecular subtypes of breast carcinoma in Saudi Arabia: aretrospective study. Saudi Med J. 2016;37(5):506e512. https://doi.org/ 10.15537/smj.2016.5.15000. [Crossref]  [PubMed]  [PMC] 
  39. Bradbury AR, Olopade OI. Genetic susceptibility to breast cancer. Rev Endocr Metab Disord. 2007;8:255e267. [Crossref]  [PubMed] 
  40. Garber JE, Goldstein AM, Kantor AF, Dreyfus MG, Fraumeni Jr JF, Li FP. Followup study of twenty-four families with LieFraumeni syndrome. Cancer Res. 1991;51:6094e6097.
  41. NCCN Clinical Practice Guidelines in Oncology. Genetic/familial High Risk Assessment: Breast and Ovarian. Version I. 2008 www.nccn.org/professionals/ physician_gls/PDF/genetics_screening.pdf.
  42. Ingvarsson S, Sigbjornsdottir BI, Huiping C, et al. Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast Cancer Res. 2002;4(3):R4. [Crossref]  [PubMed]  [PMC] 
  43. Al-Qasem Aj, Toulimat M, Eldali Am, et al. TP53 genetic alterations in Arab breast cancer patients: novel mutations, pattern and distribution. Oncol Lett. 2011;2(2):363e369. https://doi.org/10.3892/ol.2011.236. [Crossref]  [PubMed]  [PMC] 
  44. Bogdanova N, Feshchenko S, Schurmann P, et al. Nijmegen breakage syndrome mutations and risk of breast cancer. Int J Cancer. 2007;122:802e806. [Crossref]  [PubMed] 
  45. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the PeutzeJeghers syndrome. Clin Cancer Res. 2006;12:3209e3215. [Crossref]  [PubMed] 
  46. Lynch HT, Lynch JF, Lynch PM, Attard T. Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Fam Cancer. 2008;7:27e39. [Crossref]  [PubMed] 
  47. Hardie DG, Alessi DR. LKB1 and AMPK and the cancer-metabolism link - ten years after. BMC Biol. 2013 Apr 15;11:36. https://doi.org/10.1186/1741-7007- 11-36. [Crossref]  [PubMed]  [PMC] 
  48. Chen J, Lindblom A. Germline mutation screening of the STK11/LKB1 gene in familial breast cancer with LOH on 19p. Clin Genet. 2000 May;57(5):394e397. [Crossref]  [PubMed] 
  49. Alharbi KK, Khan IA, Eldesouky MH, Al-Hakeem MM, Abotalib Z. The genetic polymorphism in the STK11 does not affect gestational diabetes. Acta Biochim Pol. 2015;62(3):569e572. https://doi.org/10.18388/abp.2015_1025. [Crossref]  [PubMed] 
  50. Guenard F, Labrie Y, Ouellette G, et al. Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk nonBRCA1/2 French Canadian breast cancer families. Fam Cancer. 2007;6:483e490. [Crossref]  [PubMed] 
  51. Saal LH, Gruvberger-Saal SK, Persson C, et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet. 2008;40:102e107. [Crossref]  [PubMed]  [PMC] 
  52. Crivelli L, Bubien V, Jones N, et al. Insertion of Alu elements at a PTEN hotspot in Cowden syndrome. Eur J Hum Genet. 2017 May 17. https://doi.org/10.1038/ ejhg.2017.81.
  53. Vasen HF, Morreau H, Nortier JW. Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet. 2001;68: 1533e1535. [Crossref]  [PubMed]  [PMC] 
  54. Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007;11: 103e105. [Crossref]  [PubMed] 
  55. Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J. Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer. 1996;77: 1836e1843. [Crossref] 
  56. Geary J, Sasieni P, Houlston R, et al. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer. 2008;7:163e172. [Crossref]  [PubMed] 
  57. Watson P, Vasen HF, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123:444e449. [Crossref]  [PMC] 
  58. Howlett NG. Fanconi anemia: Fanconi anemia, breast and embryonal cancer risk revisited. Eur J Hum Genet. 2007;15:715e717. [Crossref]  [PubMed] 
  59. Lu J-Y, Sheng J-Q. Advances in the study of Lynch syndrome in China. World J Gastroenterol: WJG. 2015;21(22):6861e6871. https://doi.org/10.3748/ wjg.v21.i22.6861. [Crossref]  [PubMed]  [PMC] 
  60. Carroll SL, Stonecypher MS. Tumor suppressor mutations and growth factor signaling in the pathogenesis of NF1-associated peripheral nerve sheath tumors: II. The role of dysregulated growth factor signaling. J Neuropathol Exp Neurol. 2005 Jan;64(1):1e9. [Crossref]  [PubMed] 
  61. Sharif S, Moran A, Huson SM, et al. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet. 2007;44:481e484. [Crossref]  [PubMed]  [PMC] 
  62. Uusitalo E, Kallionp€a€a RA, Kurki S, et al. Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors. Br J Canc. 2017;116(2):211e217. https://doi.org/10.1038/bjc.2016.403. [Crossref]  [PubMed]  [PMC] 
  63. Wang X, Teer JK, Tousignant RN, et al. Breast cancer risk and germline genomic profiling of women with neurofibromatosis type 1 who developed breast cancer. Genes Chromosomes Cancer. 2018 Jan;57(1):19e27. https:// doi.org/10.1002/gcc.22503. [Crossref]  [PubMed] 
  64. Wang W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet. 2007;8:735e748. [Crossref]  [PubMed] 
  65. Hakem R. DNA-damage repair; the good, the bad, and the ugly. EMBO J. 2008;27:589e605. [Crossref]  [PubMed]  [PMC] 
  66. D'Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Canc. 2003;3:23e34. [Crossref]  [PubMed] 
  67. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995;268:1749e1753. [Crossref]  [PubMed] 
  68. Renwick A, Thompson D, Seal S, et al. ATM mutations that cause ataxiatelangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38: 873e875. [Crossref]  [PubMed] 
  69. Goldgar DE, Healey S, Dowty JG, et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011;13(4):R73. https://doi.org/10.1186/ bcr2919. [Crossref]  [PubMed]  [PMC] 
  70. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006;25:5906e5911. [Crossref]  [PubMed] 
  71. Bartek J, Falck J, Lukas J. CHK2 kinase-a busy messenger. Nat Rev Mol Cell Biol. 2001;2:877e886. [Crossref]  [PubMed] 
  72. Nevanlinna H, J Bartek J. The CHEK2 gene and inherited breast cancer susceptibility. Oncogene. 2006;25:5912e5919. https://doi.org/10.1038/ sj.onc.1209877. [Crossref]  [PubMed] 
  73. Adank MA, Hes FJ, van Zelst-Stams WA, van den Tol MP, Seynaeve C, Oosterwijk JC. CHEK2-mutation in Dutch breast cancer families: expanding genetic testing for breast cancer. Ned Tijdschr Geneeskd. 2015;159:A8910.
  74. Leedom TP, LaDuca H, McFarland R, Li S, Dolinsky JS, Chao EC. Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. Cancer Genet. 2016 Sep;209(9):403e407. https://doi.org/10.1016/j.cancergen.2016.08.005. [Crossref]  [PubMed] 
  75. De Nicolo A, Tancredi M, Lombardi G, et al. A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ line mutation impairs protein stability and function. Clin Cancer Res: Off J Amer Assoc Canc Res. 2008;14(14):4672e4680. https://doi.org/10.1158/1078-0432.CCR-08-0087. [Crossref]  [PubMed]  [PMC] 
  76. Weber-Lassalle N, Hauke J, Ramser J, et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res. 2018;20:7. https://doi.org/10.1186/s13058-018-0935-9. [Crossref]  [PubMed]  [PMC] 
  77. Gupta I, Ouhtit A, Al-Ajmi A, et al. BRIP1 overexpression is correlated with clinical features and survival outcome of luminal breast cancer subtypes. Endocrine Connections. 2018;7(1):65e77. https://doi.org/10.1530/EC-17-0173. [Crossref]  [PubMed]  [PMC] 
  78. Hofstatter EW, Domchek SM, Miron A, et al. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011;10(2). https://doi.org/ 10.1007/s10689-011-9426-1, 10.1007/s10689-011-9426-1. [Crossref]  [PubMed]  [PMC] 
  79. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39: 165e167. https://doi.org/10.1038/ng 1959. [Crossref]  [PubMed]  [PMC] 
  80. Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719e729. https:// doi.org/10.1016/j.molcel.2006.05.022. [Crossref]  [PubMed] 
  81. Reid S, Schindler D, Hanenberg H, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39:162e164. https://doi.org/10.1038/ng1947. [Crossref]  [PubMed] 
  82. Zhang F, Ma J, Wu J, et al. PALB2 Links BRCA1 and BRCA2 in the DNAdamage response. Curr Biol. 2009;19:524e529. https://doi.org/10.1016/ j.cub.2009.02.018. [Crossref]  [PubMed]  [PMC] 
  83. Byrnes GB, Southey MC, Hopper JL. Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008;10:208e214. https://doi.org/ 10.1186/bcr2099. [Crossref]  [PubMed]  [PMC] 
  84. Heikkinen T, Karkkainen H, Aaltonen K, et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res. 2009;15:3214e3222. https://doi.org/10.1158/1078- 0432.CCR-08-3128. [Crossref]  [PubMed] 
  85. Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70:7353e7359. https://doi.org/10.1158/0008- 5472.CAN-10-1012. [Crossref]  [PubMed]  [PMC] 
  86. Kinoshita E, van der Linden E, Sanchez H, Wyman C. RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function? Chromosome Res: Int J Mol Supramol Evolut Aspects Chromosome Biol. 2009;17(2):277e288. https://doi.org/10.1007/s10577-008-9018-6. [Crossref]  [PubMed]  [PMC] 
  87. Rojowska A, Lammens K, Seifert FU, Direnberger C, Feldmann H, Hopfner K-P. Structure of the Rad50 DNA double-strand break repair protein in complex with DNA. EMBO J. 2014;33(23):2847e2859. https://doi.org/10.15252/ embj.201488889. [Crossref]  [PubMed]  [PMC] 
  88. Hsu HM, Wang HC, Chen ST, Hsu GC, Shen CY, Yu JC. Breast cancer risk is associated with the genes encoding the DNA double-strand break repair Mre11/Rad50/Nbs1 complex. Cancer Epidemiol Biomark Prev. 2007 Oct;16(10): 2024e2032. [Crossref]  [PubMed] 
  89. Moffa AB, Tannheimer SL, Ethier SP. Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. Mol Canc Res. 2004;2:643e652.
  90. Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev. 2005;16:179e186. [Crossref]  [PubMed] 
  91. Moffa AB, Ethier SP. Differential signal transduction of alternatively spliced FGFR2 variants expressed in human mammary epithelial cells. J Cell Physiol. 2007;210:720e731. [Crossref]  [PubMed] 
  92. Yang YB, Zhao ZX, Huang W, Liu H, Tan YL, Wang WM. Association between fibroblast growth factor receptor-2 gene polymorphism and risk of breast cancer in Chinese populations: a HuGE review and meta-analysis. J Can Res Ther. 2016;12:543e549. [Crossref]  [PubMed] 
  93. Sahu SK, Fritz A, Tiwari N, et al. TOX3 regulates neural progenitor identity. Biochim Biophys Acta. 2016 Jul;1859(7):833e840. https://doi.org/10.1016/ j.bbagrm.2016.04.005. [Crossref]  [PubMed] 
  94. Han C-C, Yue L-L, Yang Y, Jian B-Y, Ma L-W, Liu J-C. TOX3 protein expression is correlated with pathological characteristics in breast cancer. Oncol Lett. 2016;11(3):1762e1768. https://doi.org/10.3892/ol.2016.4117. [Crossref]  [PubMed]  [PMC] 
  95. Han Y-J, Zhang J, Zheng Y, Huo D, Olopade OI. Genetic and epigenetic regulation of TOX3 expression in breast cancerSuzuki H, ed. PLoS One. 2016;11(11):e0165559. https://doi.org/10.1371/journal.pone.0165559. [Crossref]  [PubMed]  [PMC] 
  96. Easton DF, Pooley KA, Dunning AM, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447: 1087e1093.
  97. Jongstra-Bilen J, Jongstra J. Leukocyte-specific protein 1 (LSP1): a regulator of leukocyte emigration in inflammation. Immunol Res. 2006;35:65e74. [Crossref] 
  98. Chen H, Qi X, Qiu P, Zhao J. Correlation between LSP1 polymorphisms and the susceptibility to breast cancer. Int J Clin Exp Pathol. 2015;8(5):5798e5802.
  99. Jongstra-Bilen J, Jongstra J. Leukocyte-specific protein 1 (LSP1): a regulator of leukocyte emigration in inflammation. Immunol Res. 2006;35:65e74. [Crossref] 
  100. Smith AL, Ganesh L, Leung K, Jongstra-Bilen J, Jongstra J, Nabel GJ. Leukocytespecific protein 1 interacts with DC-SIGN and mediates transport of HIV to the proteasome in dendritic cells. J Exp Med. 2007;204:421e430. [Crossref]  [PubMed]  [PMC] 
  101. Koral K, Paranjpe S, Bowen WC, Mars W, Luo J, Michalopoulos GK. Leukocytespecific protein 1: a novel regulator of hepatocellular proliferation and migration deleted in human hepatocellular carcinoma. Hepatology. 2015;61: 537e547. 102. Pearlman A, Loke J, Le Caignec C, et al. Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am J Hum Genet. 2010;87(6): 898e904. https://doi.org/10.1016/j.ajhg.2010.11.003. [Crossref]  [PubMed]  [PMC] 
  102. Pham TT, Angus SP, Johnson GL. MAP3K1: genomic alterations in cancer and function in promoting cell survival or apoptosis. Genes Canc. 2013;4(11-12): 419e426. https://doi.org/10.1177/1947601913513950. [Crossref]  [PubMed]  [PMC] 
  103. Campos-Xavier B, Saraiva JM, Savarirayan R, et al. Phenotypic variability at the TGF-beta1 locus in Camurati-Engelmann disease. Hum Genet. 2001 Dec;109(6):653e658. [Crossref]  [PubMed] 
  104. Imamura T, Hikita A, Inoue Y. The roles of TGF-beta signaling in carcinogenesis and breast cancer metastasis. Breast Canc. 2012;19(2):118e124. https:// doi.org/10.1007/s12282-011-0321-2. [Crossref]  [PubMed] 
  105. Lebrun JJ. The dual role of TGFb in human cancer: from tumor suppression to cancer metastasis. ISRN Molecul Biol. 2012;7:1e28. https://doi.org/10.5402/ 2012/381428. [Crossref]  [PubMed]  [PMC] 
  106. Shin A, Shu XO, Cai Q, Gao YT, Zheng W. Genetic polymorphisms of the transforming growth factor-beta1 gene and breast cancer risk: a possible dual role at different cancer stages. Cancer Epidemiol Biomark Prev. 2005;14(6): 1567e1570. https://doi.org/10.1158/1055-9965.EPI-05-0078. [Crossref]  [PubMed] 
  107. Pardali K, Moustakas A. Actions of TGF-b as tumor suppressor and prometastatic factor in human cancer. Biochim Biophys Acta. 2007;1775:21e62. [Crossref]  [PubMed] 
  108. Inman GJ. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev. 2011;21(1):93e99. https://doi.org/10.1016/ j.gde.2010.12.004. [Crossref]  [PubMed] 
  109. Parvizi S, Mohammadzadeh G, Karimi M, Noorbehbahani M, Jafary A. Effects of two common promoter polymorphisms of transforming growth factor-b1 on breast cancer risks in ahvaz, west south of Iran. Iran J Cancer Prev. 2016;9(1):e5266. https://doi.org/10.17795/ijcp-5266. [Crossref]  [PMC] 
  110. Yao Y, Zhao K, Yu Z, et al. Wogonoside inhibits invasion and migration through suppressing TRAF2/4 expression in breast cancer. J Exp Clin Canc Res: CR. 2017;36:103. https://doi.org/10.1186/s13046-017-0574-5. [Crossref]  [PubMed]  [PMC] 
  111. Stope MB, Weiss M, Koensgen D, et al. Y-box binding protein-1 enhances oncogenic transforming growth factor b signaling in breast cancer cells via triggering phospho-activation of Smad 2. Anticancer Res. 2017 Dec;37(12): 6745e6748. [Crossref] 
  112. Uzunoglu H, Korak T, Ergul E, et al. Association of the nibrin gene (NBN) variants with breast cancer. Biomed Rep. 2016;4(3):369e373. https://doi.org/ 10.3892/br.2016.579. [Crossref]  [PubMed]  [PMC] 
  113. Damiola F, Pertesi M, Oliver J, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation- screening study. Breast Cancer Res. 2014;16(3):R58. https://doi.org/ 10.1186/bcr3669. [Crossref]  [PubMed]  [PMC]