Expressions of HIF-1α and CA9 in breast carcinoma and their relationships with basal-like subtype

doi:10.3760/cma.j.issn.1673-422X.2017.06.004

Abstract

Abstract: ObjectiveTo study the expressions of hypoxia inducible factor1α (HIF1α) and carbonic anhydrase 9 (CA9) in different molecular subtypes of breast carcinoma and their relationships with basallike subtype. MethodsThe expressions of HIF1α and CA9 were detected by immunohistochemistry in five subtypes of breast carcinoma （n=803）. The relationships of the expressions of HIF1α and CA9 with the clinicopathologic parameters of basallike subtype and with the prognosis of patients were analyzed. ResultsThe positive expression rates of HIF1α and CA9 protein in breast carcinoma were much higher than those in paratumor breast tissues (43.96% vs. 3.86%, χ2=354.858, P<0.001; 19.80% vs. 4.61%, χ2=86.495, P<0.001). The positive expression rates of HIF1α in Luminal A, Luminal B, epidermal growth factor receptor2 (HER2) overexpression, basallike and normal breastlike subtypes were 31.97%, 25.00%, 56.06%, 77.89% and 55.76% respectively, and the positive expression rates of CA9 were 7.48%, 5.56%, 60.61%, 40.00% and 27.88% respectively, with significant differences (χ2=88.628, P＜0.001; χ2=147.128, P＜0.001). The positive expression rates of HIF1α and CA9 in estrogen receptor (ER)negative breast carcinomas (HER2 overexpression, basallike and normal breastlike) were significantly higher than those in ERpositive subtypes (Luminal A and Luminal B, all P<0.005). There was a significant positive correlation between HIF1α and CA9 (C=0.315, P=0.001), and both were correlated with the lymph node metastasis (χ2=4.542, P=0.033; χ2=7.025, P=0.008), pTNM stage (χ2=5.390, P=0.020; χ2=10.179, P=0.001) and poor prognosis (χ2=4.353, P=0.037; χ2=6.056, P=0.014) of basallike subtype. ConclusionOverexpressions of HIF1α and CA9 may be related to the ERnegative breast cancer more closely, and both may play important roles in the occurrence and development of basallike subtype. Overexpressions of HIF1α and CA9 may suggest the poorer prognosis of patients with basallike breast carcinoma.

Key words: Breast neoplasms, Hypoxiainducible factor 1, alpha subunit, Carbonic anhydrases, Basallike subtype

Sun Jirui, Zhou Bingjuan, Chen Hong, Ma Qiushuang, Zhang Jinku, Sun Zhe, Zhang Dongchen. Expressions of HIF-1α and CA9 in breast carcinoma and their relationships with basal-like subtype[J]. Journal of International Oncology, 2017, 44(6): 415-.

References

［1］ Zuo TT, Zheng RS, Zeng HM, et al. Female breast cancer incidence and mortality in China, 2013［J］. Thorac Cancer, 2017, 8(3): 214-218. DOI: 10.111/17597714. ［2］ Fan L, StrasserWeippl K, Li JJ, et al. Breast cancer in China［J］. Lancet Oncol, 2014, 15(7): e279-e289. DOI: 10.1016/S14702045(13)705679. ［3］ Adams JM, Difazio LT, Rolandelli RH, et al. HIF1: a key mediator in hypoxia［J］. Acta Physiol Hung, 2009, 96(1): 19-28. DOI: 10.1556/APhysiol.96.2009.1.2. ［4］ Hynninen P, Parkkila S, Huhtala H, et al. Carbonic anhydrase isozymes Ⅱ, Ⅸ, and Ⅻ in uterine tumors［J］. APMIS, 2012, 120(2): 117-129. DOI: 10.1111/j.16000463.2011.02820.x. ［5］ Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basallike subtype of invasive breast carcinoma［J］. Clin Cancer Res, 2004, 10(16): 53675374. DOI: 10.1158/10780432.CCR040220. ［6］ Zhong H, De Marzo AM, Laughner E, et al. Overexpression of hypoxiainducible factor 1 alpha in common human cancers and their metastases［J］. Cancer Res, 1999, 59(22): 5830-5835. ［7］ Meier V, Guscetti F, Roos M, et al. HypoxiaRelated marker GLUT1, CAIX, proliferative index and microvessel density in canine oral malignant neoplasia［J］. PLoS One, 2016, 11(2): e0149993. DOI: 10.1371/journal.pone.0149993. ［8］ Ji RC. Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis［J］. Cancer Lett, 2013, 346(1): 6-16. DOI: 10.1016/j.canlet.2013.12.001. ［9］ Hu Y, Liu J, Huang H. Recent agents targeting HIF1α for cancer therapy［J］. J Cell Biochem, 2013, 114(3): 498-509. DOI: 10.1002/jcb.24390. ［10］ Rankin EB, Giaccia AJ. The role of hypoxiainducible factors in tumorigenesis［J］. Cell Death Differ, 2008, 15(4): 678-685. DOI: 10.1038/cdd.2008.21. ［11］ Kitagawa N, Kondo S, Wakisaka N, et al. Expression of seveninabsentia homologue 1 and hypoxiainducible factor 1 alpha: novel prognostic factors of nasopharyngeal carcinoma［J］. Cancer Lett, 2013, 331(1): 52-57. DOI: 10.1016/j.canlet.2012.12.002. ［12］ Pastoreková S, Parkkila S, Parkkila AK, et al. Carbonic anhydrase Ⅸ, MN/CA Ⅸ: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts［J］. Gastroenterology, 1997, 112(2): 398-408. ［13］ Yang JS, Lin CW, Chuang CY, et al. Carbonic anhydrase Ⅸ overexpression regulates the migration and progression in oral squamous cell carcinoma［J］. Tumour Biol, 2015, 36(12): 9517-9524. DOI: 10.1007/s1327701536928. ［14］ Chen Y, Li X, Wu S, et al. Expression of HIF1α and CAIX in nasopharyngeal carcinoma and their correlation with patients′ prognosis［J］. Med Oncol, 2014, 31(12): 304. DOI: 10.1007/s1203201403041. ［15］ Li M, Song J, Pytel P. Expression of HIF1 regulated proteins vascular endothelial growth factor, carbonic anhydrase Ⅸ and hypoxia inducible gene 2 in hemangioblastomas［J］. Folia Neuropathol, 2014, 52(3): 234-242. ［16］袁媛, 张赟, 高宇哲, 等. HIF1α及EMT在不同分子亚型乳腺浸润性导管癌中的表达及意义［J］. 中国妇幼保健, 2015, 30(29): 5054-5058. DOI: 10.7620/zgfybj.j.issn.10014411.2015.29.49. ［17］ Giatromanolaki A, Koukourakis MI, Sivridis E, et al. Expression of hypoxiainducible carbonic anhydrase9 relates to angiogenic pathways and independently to poor outcome in nonsmall cell lung cancer［J］. Cancer Res, 2001, 61(21): 7992-7998. ［18］ Bartosová M, Parkkila S, Pohlodek K, et al. Expression of carbonic anhydrase Ⅸ in breast is associated with malignant tissues and is related to overexpression of cerbB2［J］. J Pathol, 2002, 197(3): 314-321. ［19］ Sadlecki P, Bodnar M, Grabiec M, et al. The role of hypoxiainducible factor1α, glucose transporter1, (GLUT1) and carbon anhygrase Ⅸ in endometrial cancer patients［J］. Biomed Res Int, 2014, 2014: 616850. DOI: 10.1155/2014/616850. ［20］ Eckert AW, Lautner MH, Schütze A, et al. Coexpression of Hif1alpha and CAIX is associated with poor prognosis in oral squamous cell carcinoma patients［J］. J Oral Pathol Med, 2010, 39(4): 313-317. DOI: 10.1111/j.16000714.2009.00829.x. ［21］ Lendahl U, Lee KL, Yang H, et al. Generating specificity and diversity in the transcriptional response to hypoxia［J］. Nat Rev Genet, 2009, 10(12): 821-832. DOI: 10.1038/nrg2665. ［22］ Vleugel MM, Greijer AE, Shvarts A, et al. Differential prognostic impact of hypoxia induced and diffuse HIF1 alpha expression in invasive breast cancer［J］. J Clin Pathol, 2005, 58(2): 172-177. DOI: 10.1136/jcp.2004.019885. ［23］ Chiche J, Rouleau M, Gounon PA, et al. Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli［J］. J Cell Physiol, 2010, 222(3): 648-657. DOI: 10.1002/jcp.21984. ［24］ Jain RK. Transport of molecules, particles, and cells in solid tumors［J］. Annu Rev Biomed Eng, 1999, 1: 241-263. DOI: 10.1146/annurev.bioeng.1.1.241. ［25］ Wang HB, Zhang HJ, Su JM, et al. Epithelialmesenchymal transition (EMT) and its effect on microRNA expression in lung cancer［J］. Zhonghua Zhong Liu Za Zhi, 2011, 33(8): 590-593.

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