Differential relationship between two hypoxia markers: HIF-1α and GLUT1 and classic prognostic factors in invasive breast carcinoma

• Authors: Agnieszka Żyromska , Hanna Andrusewicz , Joanna Łysik , Wojciech Jóźwicki , Tomasz Wiśniewski

Title variants

PL

Zróżnicowana zależność pomiędzy dwoma markerami hipoksji: HIF-1α i GLUT1 aklasycznymi czynnikami prognostycznymi w inwazyjnym raku piers

• Languages of publication: EN

Abstracts

EN

Background: Tumor hypoxia is an adverse prognostic factor which promotes cancer aggressiveness and limits its radio- and chemosensitivity. The aim of our study was to explore the relationship between endogenous hypoxia markers and classic prognostic factors, including clinical stage and the expression of ER, PR, and HER2 in primary untreated breast carcinoma. Methods: A retrospective immunohistochemical analysis of archived tissue blocks collected from 153 women, who underwent total mastectomy and lymph node dissection, included the expression of two hypoxia-related proteins: HIF-1α and GLUT1. Results: GLUT1 labelling index (LI) showed a positive correlation with T stage (R = 0.18, p = 0.026) and HER2 status (R = 0.25, p = 0.002), and a negative correlation with the expression of ER (R = −0.19, p = 0.017) and PR (R = −0.17, p = 0.032). HIF-1α LI showed a positive correlation with ER expression (R = 0.16, p = 0.045). In the multivariate regression analysis, a different relationship between classic prognostic factors and the two tested hypoxia proteins was proven. Higher GLUT1 expression correlated with ER and PR negativity (p = 0.02 and p = 0.01, respectively) as well as with higher expression of HER2 (p = 0.04). HIF-1α showed no association with PR and HER2, but a positive correlation with ER (p = 0.02). Neither of the hypoxia proteins was associated with a tumor grade. Only one clinical feature, T stage, correlated with both of the hypoxia markers: positively with GLUT1 (p = 0.049) and negatively with HIF-1α (p = 0.01) expression. Conclusions: In breast cancer, GLUT1 expression may be considered an additional prognostic factor which correlates with an adverse status of HER2 and hormonal receptors, and indicates a more hypoxic, radio- and chemotherapy refractory profile of carcinoma.

PL

Tło: Hipoksja w  guzie nowotworowym stanowi niekorzystny czynnik prognostyczny, ogranicza jego promienioi chemiowrażliwość oraz promuje bardziej agresywny przebieg choroby. Przewidywanie rokowania i odpowiedzi na leczenie wymaga wiedzy o związku hipoksji z uznanymi czynnikami prognostycznymi. Celem badania było określenie zależności pomiędzy endogennymi markerami hipoksji w  pierwotnym przewodowym raku piersi a  klasycznymi czynnikami prognostycznymi, takimi jak stopień zaawansowania klinicznego oraz ekspresja receptorów ER, PR i HER2. Metody: Retrospektywna analiza immunohistochemiczna archiwizowanych bloczków tkanek pobranych od 153 kobiet, poddanych mastektomii i limfadenektomii pachowej, objęła ekspresję dwóch związanych z hipoksją białek: HIF-1α i GLUT1. Wyniki: Indeks wiązania GLUT1 (GLUT1 LI) wykazał korelację dodatnią z wielkością guza (R = 0,18, p = 0,026) i ekspresją HER2 (R = 0,25, p = 0,002) oraz ujemną z ekspresją ER (R = −0,19, p = 0,017) i PR (R = −0,17, p = 0,032). HIF-1α LI korelował wyłącznie z ekspresją ER (R = 0,16, p = 0,045). W analizie wieloczynnikowej wykazano zróżnicowaną zależność pomiędzy klasycznymi czynnikami prognostycznymi i testowanymi markerami hipoksji. GLUT1 LI korelował negatywnie z ekspresją ER i PR (odpowiednio p = 0,02 i p = 0,01) oraz pozytywnie z ekspresją HER2 (p = 0,04). Nie udowodniono korelacji pomiędzy HIF-1α LI a ekspresją PR czy HER2, natomiast wykazano jego dodatnią zależność z ekspresją ER (p = 0,02). Żaden marker hipoksji nie korelował ze stopniem zróżnicowania histologicznego nowotworu. Tylko jeden kliniczny czynnik – wielkość guza (T) – korelował z ekspresją badanych białek: dodatnio z GLUT1 (p = 0,049), a ujemnie z HIF-1α (p = 0,01). Wnioski: Ekspresja GLUT1 w raku piersi może stanowić dodatkowy czynnik prognostyczny, korelujący z niekorzystnym statusem receptora HER2 i receptorów hormonalnych oraz wskazywać na bardziej hipoksyczny, oporny na radioi chemioterapię, profil raka.

Keywords

EN

GLUT1; HIF-1α; hypoxia; immunohistochemistry; prognostic factors

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Current Gynecologic Oncology
• Year: 2016
• Volume: 14
• Issue: 4
• Pages: 197–203

Contributors

author

Agnieszka Żyromska

• Department of Oncology and Brachytherapy, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Poland; Department of Radiotherapy, Prof. Francis Łukaszczyk Oncology Center, Bydgoszcz, Poland

author

Hanna Andrusewicz

• Department of Tumor Pathology and Pathomorphology, Prof. Francis Łukaszczyk Oncology Center, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland

author

Joanna Łysik

• Department of Tumor Pathology and Pathomorphology, Prof. Francis Łukaszczyk Oncology Center, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland

author

Wojciech Jóźwicki

• Department of Tumor Pathology and Pathomorphology, Prof. Francis Łukaszczyk Oncology Center, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland

author

Tomasz Wiśniewski

• Department of Oncology and Brachytherapy, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Poland; Department of Radiotherapy, Prof. Francis Łukaszczyk Oncology Center, Bydgoszcz, Poland

References

• 1. Vaupel P, Mayer A, Briest S et al.: Hypoxia in breast cancer: role of blood flow, oxygen diffusion distances, and anemia in the development of oxygen depletion. Adv Exp Med Biol 2005; 566: 333–342.
• 2. Eriksen JG, Horsman MR: Tumour hypoxia – a characteristic feature with a complex molecular background. Radiother Oncol 2006; 81: 119–121.
• 3. Shibaji T, Nagao M, Ikeda N et al.: Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res 2003; 23: 4721–4727.
• 4. Kurokawa T, Miyamoto M, Kato K et al.: Overexpression of hypoxia-inducible-factor 1α (HIF-1α) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer 2003; 89: 1042–1047.
• 5. Beasley NJ, Leek R, Alam M et al.: Hypoxia-inducible factors HIF-1α and HIF-2α in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res 2002; 62: 2493–2497.
• 6. Volm M, Koomägi R: Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res 2000; 20: 1527–1533.
• 7. Bos R, Zhong H, Hanrahan CF et al.: Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001; 93: 309–314.
• 8. Bos R, van der Groep P, Greijer AE et al.: Levels of hypoxiainducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer 2003; 97: 1573–1581.
• 9. Ivan M, Kondo K, Yang H et al.: HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292: 464–468.
• 10. Kaelin WG Jr, Ratcliffe PJ: Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008; 30: 393–402.
• 11. Shaw RJ: Glucose metabolism and cancer. Curr Opin Cell Biol 2006; 18: 598–608.
• 12. Grover-McKay M, Walsh SA, Seftor EA et al.: Role for glucose transporter 1 protein in human breast cancer. Pathol Oncol Res 1998; 4: 115–120.
• 13. Stackhouse BL, Williams H, Berry P et al.: Measurement of Glut-1 expression using tissue microarrays to determine a race specific prognostic marker for breast cancer. Breast Cancer Res Treat 2005; 93: 247–253.
• 14. Andrusewicz H, Żyromska A, Makarewicz R: Wpływ nasilenia hipoksji i unaczynienia w guzie pierwotnym na występowanie klasycznych czynników rokowniczych u chorych na raka gruczołu krokowego – czy markery biologiczne są pomocne w przewidywaniu przebiegu choroby nowotworowej? Współcz Onkol 2009; 13: 90–94.
• 15. Makarewicz R, Zyromska A, Andrusewicz H: Comparative analysis of biological profiles of benign prostate hyperplasia and prostate cancer as potential diagnostic, prognostic and predictive indicators. Folia Histochem Cytobiol 2011; 49: 452–457.
• 16. Keith B, Johnson RS, Simon MC: HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 2011; 12: 9–22.
• 17. Díaz M, Vraskou Y, Gutiérrez J et al.: Expression of rainbow trout glucose transporters GLUT1 and GLUT4 during in vitro muscle cell differentiation and regulation by insulin and IGF-I. Am J Physiol Regul Integr Comp Physiol 2009; 296: R794–R800.
• 18. Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E: The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 2004; 64: 2627–2633.
• 19. Yun J, Rago C, Cheong I et al.: Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 2009; 325: 1555–1559.
• 20. Silva A, Gírio A, Cebola I et al.: Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells. Leukemia 2011; 25: 960–967.
• 21. Wang GL, Jiang BH, Rue EA et al.: Hypoxia-inducible factor 1 is a basic–helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995; 92: 5510–5514.
• 22. Zundel W, Schindler C, Haas-Kogan D et al.: Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000; 14: 391–396.
• 23. Shafee N, Kaluz S, Ru N et al.: PI3K/Akt activity has variable cellspecific effects on expression of HIF target genes, CA9 and VEGF, in human cancer cell lines. Cancer Lett 2009; 282: 109–115.
• 24. Montagner M, Enzo E, Forcato M et al.: SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxiainducible factors. Nature 2012; 487: 380–384.
• 25. Surazynski A, Miltyk W, Prokop I et al.: The effect of estrogen on prolidase-dependent regulation of HIF-1α expression in breast cancer cells. Mol Cell Biochem 2013; 379: 29–36.
• 26. Koda M, Kanczuga-Koda L, Sulkowska M et al.: Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy. BMC Cancer 2010; 10: 320.
• 27. Choi J, Jung WH, Koo JS: Metabolism-related proteins are differentially expressed according to the molecular subtype of invasive breast cancer defined by surrogate immunohistochemistry. Pathobiology 2013; 80: 41–52.
• 28. Adams A, van Brussel AS, Vermeulen JF et al.: The potential of hypoxia markers as target for breast molecular imaging – a systematic review and meta-analysis of human marker expression. BMC Cancer 2013; 13: 538.
• 29. Noguchi Y, Saito A, Miyagi Y et al.: Suppression of facilitative glucose transporter 1 mRNA can suppress tumor growth. Cancer Lett 2000; 154: 175–182.
• 30. Chan JY, Kong SK, Choy YM et al.: Inhibition of glucose transporter gene expression by antisense nucleic acids in HL-60 leukemia cells. Life Sci 1999; 65: 63–70.

• Document Type: article