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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Molecular Evaluation of HIF-1α Gene Variation and Determination of Its Frequency and Association with Breast Cancer Susceptibility in Saudi Arabia

Author(s): Rashid Mir*, Faisel M. Abu-Duhier and Ibrahim A. Albalawi

Volume 21, Issue 3, 2021

Published on: 10 September, 2020

Page: [544 - 553] Pages: 10

DOI: 10.2174/1871530320666200910105214

Price: $65

Abstract

Aim: Hypoxia-inducible factor 1 (HIF-1α) is responsible in regulating oxygen homeostasis in tissues and is a central effector of the hypoxic response besides its protein overexpression has been shown to have prognostic relevance in several cancers including breast cancer. Several reports indicated that HIF-1α gene variation C1772T (Pro582Ser) is associated with increased breast susceptibility but results remained controversial. Therefore, we performed the molecular evaluation of HIF-1α gene variation and determined its frequency and association with Breast Cancer susceptibility in Saudi Arabia.

Methods: This study was conducted on histologically confirmed Breast cancer patients and gender matched healthy women. HIF-1α C1772T (Pro582Ser) genotyping was done by Amplification refractory mutation system PCR method. The HIF-1α gene genotypes were correlated with different clinicopathological characteristics of breast cancer patients.

Results: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro582Ser) between breast cancer cases and gender matched healthy controls (P=0.010). Our findings showed that the HIF- 1α variant was associated with an increased risk of Breast cancer for HIF-1α CC vs CT genotype OR = 2.20, 95% CI = (1.28 -3.77), P = 0.004) in codominant inheritance model. The significant association was reported for HIF1A for genotypes CC vs (CT+ TT) OR = 1.98, 95% CI = (1.17-3.34), P = 0.010) in dominant inheritance model tested. In case of recessive inheritance model, a non-significant association of HIF-1 alpha gene variants was reported for (CC+ CT) vs TT) OR = 1.03, 95% CI = (0. 064-16.79), P = 0.97). During the allelic comparison, a non-significant association was reported between A vs C allele among Breast cancer patients. A significant association of HIF- 1α polymorphism was reported with stage as well as distant metastasis of the disease.

Conclusion: A significant difference was observed in genotype distribution of HIF-1α gene variation C1772T (Pro>Ser) between breast cancer cases and gene matched healthy controls (P=0.010). HIF-1α- CT heterozygosity and CC genotype increased the susceptibility .The HIF-1α polymorphism was reported to be significantly associated with the distant metastasis of Breast cancer. Further studies with larger data set and well-designed models are required to validate our findings.

Keywords: Hypoxia-inducible factor 1 (HIF-1), breast cancer, amplification refractory mutation system PCR, susceptibility, gene variation, Saudi Arabia

Graphical Abstract
[1]
Bray, F.; Ren, J.S.; Masuyer, E.; Ferlay, J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int. J. Cancer, 2013, 132(5), 1133-1145.
[http://dx.doi.org/10.1002/ijc.27711] [PMID: 22752881]
[2]
Albalawi, I.A.; Mir, R.; Abu Duhier, F.M. Genetic effects of vascular endothelial growth factor A (VEGF-A) and its association with disease progression in breast cancer population of Saudi Arabia. Asian Pac. J. Cancer Prev., 2020, 21(1), 139-145.
[http://dx.doi.org/10.31557/APJCP.2020.21.1.139] [PMID: 31983176]
[3]
Mir, R.; Javid, J.; Al Balawi, I.A.; Alkharsah, K.R.; Hadi, M.A.; Rahman, M.A.; Hamoud, E.; Al Alawi, Y.; Al Zahrani, A.B.M.; Abu-Duhier, F.M. A Germline mutation in the BRCA1 3’UTR variant predicts susceptibility to breast cancer in a Saudi Arabian population. Asian Pac. J. Cancer Prev., 2018, 19(3), 859-866.
[PMID: 29582646]
[4]
Albalawi, I.A.; Mir, R.; Abu-Duhier, F.M. Molecular evaluation of PROGINS mutation in progesterone receptor gene and determination of its frequency, distribution pattern and association with breast cancer susceptibility in Saudi Arabia. Endocr. Metab. Immune Disord. Drug Targets, 2020, 20(5), 760-770.
[http://dx.doi.org/10.2174/1871530319666191125153050] [PMID: 31763970]
[5]
Vaupel, P. Prognostic potential of the pre-therapeutic tumor oxygenation status. Adv. Exp. Med. Biol., 2009, 645, 241-246.
[http://dx.doi.org/10.1007/978-0-387-85998-9_36] [PMID: 19227477]
[6]
Tanimoto, K.; Yoshiga, K.; Eguchi, H.; Kaneyasu, M.; Ukon, K.; Kumazaki, T.; Oue, N.; Yasui, W.; Imai, K.; Nakachi, K.; Poellinger, L.; Nishiyama, M. Hypoxia-inducible factor-1alpha polymorphisms associated with enhanced transactivation capacity, implying clinical significance. Carcinogenesis, 2003, 24(11), 1779-1783.
[http://dx.doi.org/10.1093/carcin/bgg132] [PMID: 12919954]
[7]
G L Semenza , M K Nejfelt, S M Chi, S E Antonarakis .Hypoxiainducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene . Proc Natl Acad Sci U S A . 1991 Jul 1;88(13):5680-4..
[http://dx.doi.org/10.1073/pnas.88.13.5680]] [PMID: 2062846]
[8]
Smaldone, M.C.; Maranchie, J.K. Clinical implications of hypoxia inducible factor in renal cell carcinoma. Urol. Oncol., 2009, 27(3), 238-245.
[http://dx.doi.org/10.1016/j.urolonc.2007.12.001] [PMID: 19414111]
[9]
Choi, J.H.; Cho, H.K.; Choi, Y.H.; Cheong, J. Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1alpha in hepatocytes. Biochem. J., 2009, 424(2), 285-296.
[http://dx.doi.org/10.1042/BJ20090371] [PMID: 19712049]
[10]
Li, Y.; Li, C.; Shi, H.; Lou, L.; Liu, P. The association between the rs11549465 polymorphism in the hif-1α gene and cancer risk: a meta-analysis. Int. J. Clin. Exp. Med., 2015, 8(2), 1561-1574.
[PMID: 25932084]
[11]
Huang, C.J.; Lian, S.L.; Hou, M.F.; Chai, C.Y.; Yang, Y.H.; Lin, S.F.; Chang, H.W. SNP 1772 C > T of HIF-1α gene associates with breast cancer risk in a Taiwanese population. Cancer Cell Int., 2014, 14(1), 87.
[http://dx.doi.org/10.1186/s12935-014-0087-7] [PMID: 25302049]
[12]
Kafshdooz, L.; Tabrizi, A.D.; Mohaddes, S.M.; Kafshdooz, T.; Akbarzadeh, A.; Ghojazadeh, M.; Gharesouran, J. The polymorphism of hypoxia-inducible factor-1a gene in endometrial cancer. Asian Pac. J. Cancer Prev., 2014, 15(23), 10393-10396.
[http://dx.doi.org/10.7314/APJCP.2014.15.23.10393] [PMID: 25556481]
[13]
Badowska-Kozakiewicz, A.M.; Sobol, M.; Patera, J. Expression of multidrug resistance protein P-glycoprotein in correlation with markers of hypoxia (HIF-1α, EPO, EPO-R) in invasive breast cancer with metastasis to lymph nodes. Arch. Med. Sci., 2017, 13(6), 1303-1314.
[http://dx.doi.org/10.5114/aoms.2016.62723] [PMID: 29181060]
[14]
He, P.; Han, Q.; Liu, J.; Liu, D.; Zhao, X.; Hu, T.; Jiang, L.; Dan, H.; Zeng, X.; Li, J.; Wang, J.; Chen, Q. The association between hypoxia-inducible factor-1 α gene C1772T polymorphism and cancer risk: a meta-analysis of 37 case-control studies. PLoS One, 2013, 8(12)e83441
[http://dx.doi.org/10.1371/journal.pone.0083441] [PMID: 24367595]
[15]
Meka, P.B.; Cingeetham, A.; Nanchari, S.R.; Damineni, S.; Tipirisetti, N.; Gorre, M.; Jarjapu, S.; Annamaneni, S.; Digumarthi, R.; Satti, V. HIF-1α (1772C>T) polymorphism as marker for breast cancer development. Tumour Biol., 2015, 36(5), 3215-3220.
[http://dx.doi.org/10.1007/s13277-014-2949-y] [PMID: 25510668]
[16]
Ren, H.T.; Wang, X.J.; Kang, H.F.; Lin, S.; Wang, M.; Dai, Z.J. Associations between C1772T polymorphism in hypoxia-inducible factor-1α gene and breast cancer: a meta-analysis. Med. Sci. Monit., 2014, 20, 2578-2583.
[http://dx.doi.org/10.12659/MSM.892374] [PMID: 25484025]
[17]
Schindl, M.; Schoppmann, S.F.; Samonigg, H.; Hausmaninger, H.; Kwasny, W.; Gnant, M.; Jakesz, R.; Kubista, E.; Birner, P.; Oberhuber, G. Austrian breast and colorectal cancer study group. overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin. Cancer Res., 2002, 8(6), 1831-1837.
[PMID: 12060624]
[18]
Yamamoto, Y.; Ibusuki, M.; Okumura, Y.; Kawasoe, T.; Kai, K.; Iyama, K.; Iwase, H. Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res. Treat., 2008, 110(3), 465-475.
[http://dx.doi.org/10.1007/s10549-007-9742-1] [PMID: 17805961]
[19]
Bos, R.; van der Groep, P.; Greijer, A.E.; Shvarts, A.; Meijer, S.; Pinedo, H.M.; Semenza, G.L.; van Diest, P.J.; van der Wall, E. Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer, 2003, 97(6), 1573-1581.
[http://dx.doi.org/10.1002/cncr.11246] [PMID: 12627523]
[20]
Zhong, H.; De Marzo, A.M.; Laughner, E.; Lim, M.; Hilton, D.A.; Zagzag, D.; Buechler, P.; Isaacs, W.B.; Semenza, G.L.; Simons, J.W. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res., 1999, 59(22), 5830-5835.
[PMID: 10582706]
[21]
Li, P.; Cao, Q.; Shao, P.F.; Cai, H.Z.; Zhou, H.; Chen, J.W.; Qin, C.; Zhang, Z.D.; Ju, X.B.; Yin, C.J. Genetic polymorphisms in HIF1A are associated with prostate cancer risk in a Chinese population. Asian J. Androl., 2012, 14(6), 864-869.
[http://dx.doi.org/10.1038/aja.2012.101] [PMID: 23042446]
[22]
Semenza, G.L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer, 2003, 3(10), 721-732.
[http://dx.doi.org/10.1038/nrc1187] [PMID: 13130303]
[23]
Sun, S.; Ma, J.; Xie, P.; Wu, Z.; Tian, X. Hypoxia-responsive miR-141-3p is involved in the progression of breast cancer via mediating the HMGB1/HIF-1α signaling pathway. J. Gene Med., 2020, 22(10)e3230
[http://dx.doi.org/10.1002/jgm.3230] [PMID: 32436353]
[24]
Kim, H.O.; Jo, Y.H.; Lee, J.; Lee, S.S.; Yoon, K.S. The C1772T genetic polymorphism in human HIF-1alpha gene associates with expression of HIF-1alpha protein in breast cancer. Oncol. Rep., 2008, 20(5), 1181-1187.
[PMID: 18949419]
[25]
Lee, J.Y.; Choi, J.Y.; Lee, K.M.; Park, S.K.; Han, S.H.; Noh, D.Y.; Ahn, S.H.; Kim, D.H.; Hong, Y.C.; Ha, E.; Yoo, K.Y.; Ambrosone, C.B.; Kang, D. Rare variant of hypoxia-inducible factor-1alpha (HIF-1A) and breast cancer risk in Korean women. Clin. Chim. Acta, 2008, 389(1-2), 167-170.
[http://dx.doi.org/10.1016/j.cca.2007.12.005] [PMID: 18160046]
[26]
Apaydin, I.; Konac, E.; Onen, H.I.; Akbaba, M.; Tekin, E.; Ekmekci, A. Single nucleotide polymorphisms in the hypoxia-inducible factor-1alpha (HIF-1alpha) gene in human sporadic breast cancer. Arch. Med. Res., 2008, 39(3), 338-345.
[http://dx.doi.org/10.1016/j.arcmed.2007.11.012] [PMID: 18279708]
[27]
Konac, E.; Onen, H.I.; Metindir, J.; Alp, E.; Biri, A.A.; Ekmekci, A. An investigation of relationships between hypoxia-inducible factor-1 alpha gene polymorphisms and ovarian, cervical and endometrial cancers. Cancer Detect. Prev., 2007, 31(2), 102-109.
[http://dx.doi.org/10.1016/j.cdp.2007.01.001] [PMID: 17418979]
[28]
Naidu, R.; Har, Y.C.; Taib, N.A. Associations between hypoxia-inducible factor-1alpha (HIF-1alpha) gene polymorphisms and risk of developing breast cancer. Neoplasma, 2009, 56(5), 441-447.
[http://dx.doi.org/10.4149/neo_2009_05_441] [PMID: 19580347]
[29]
Zagouri, F.; Sergentanis, T.N.; Gazouli, M.; Tsigginou, A.; Dimitrakakis, C.; Papaspyrou, I.; Eleutherakis-Papaiakovou, E.; Chrysikos, D.; Theodoropoulos, G.; Zografos, G.C.; Antsaklis, A.; Dimopoulos, A.M.; Papadimitriou, C.A. HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case-control study. Mol. Biol. Rep., 2012, 39(12), 10873-10879.
[http://dx.doi.org/10.1007/s11033-012-1984-2] [PMID: 23065205]
[30]
Li, H.N.; He, T.; Zha, Y.J.; Du, F.; Liu, J.; Lin, H.R.; Yang, W.Z. HIF-1α rs11549465 C>T polymorphism contributes to increased cancer susceptibility: evidence from 49 studies. J. Cancer, 2019, 10(24), 5955-5963.
[http://dx.doi.org/10.7150/jca.35716] [PMID: 31762805]
[31]
Li, Y. Chunyan Li1, Hui Shi, Lieming Lou, Pengcheng Liu. The association between the rs11549465 polymorphism in the hif-1α gene andcancer risk: a meta-analysis. Int. J. Clin. Exp. Med., 2015, 8(2), 1561-1574.
[PMID: 25932084]
[32]
Koshiji, M.; To, K.K.; Hammer, S.; Kumamoto, K.; Harris, A.L.; Modrich, P.; Huang, L.E. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol. Cell, 2005, 17(6), 793-803.
[http://dx.doi.org/10.1016/j.molcel.2005.02.015] [PMID: 15780936]
[33]
Huang, L.E.; Bindra, R.S.; Glazer, P.M.; Harris, A.L. Hypoxia-induced genetic instability--a calculated mechanism underlying tumor progression. J. Mol. Med. (Berl.), 2007, 85(2), 139-148.
[http://dx.doi.org/10.1007/s00109-006-0133-6] [PMID: 17180667]
[34]
Yang, X.; Zhu, H.C.; Zhang, C.; Qin, Q.; Liu, J.; Xu, L.P.; Zhao, L.J.; Zhang, Q.; Cai, J.; Ma, J.X.; Cheng, H.Y.; Sun, X.C. HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk: an updated meta-analysis from 34 case-control studies. PLoS One, 2013, 8(11)e80396
[http://dx.doi.org/10.1371/journal.pone.0080396] [PMID: 24260383]
[35]
Shan, C.; Zheng, Y.; Wang, M.; Lin, S.; Tian, T.; Deng, Y.; Xu, P.; Hao, Q.; Wu, Y.; Yang, T.; Guo, Y.; Dai, Z. Polymorphisms in HIFs and breast cancer sutarsceptibility in Chinese women: a case-control study. Biosci. Rep., 2018, 38(5)BSR20180950
[http://dx.doi.org/10.1042/BSR20180950] [PMID: 30135144]
[36]
Ribeiro, A.L.; Gaspar, J.F.; Pereira, T.; Ribeiro, V. Lack of relevance of HIF-1α polymorphisms in breast cancer in a Portuguese population. Anticancer Res., 2013, 33(6), 2549-2555.
[PMID: 23749907]
[37]
Al Balawi, I.A.; Mir, R.; Abu-Duhier, F.M. Potential impact of vascular endothelial growth factor gene variation (-2578C>A) on breast cancer susceptibility in Saudi Arabia: a case-control study. Asian Pac. J. Cancer Prev., 2018, 19(4), 1135-1143.
[PMID: 29699375]

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