Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer


Autoři: Annika Jögi aff001;  Anna Ehinger aff002;  Linda Hartman aff002;  Sara Alkner aff002
Působiště autorů: Department of Laboratory Medicine, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden aff001;  Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund, Sweden aff002;  Lund University, Department of Clinical Genetics and Pathology, Medical Service, Regional Laboratories, Lund, Sweden aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226150

Souhrn

Background

Adjuvant endocrine treatment improves survival after estrogen receptor (ER) positive breast cancer. Recurrences occur, and most patients with metastatic breast cancer develop treatment resistance and incurable disease. An influential factor in relation to endocrine treatment resistance is tumor hypoxia and the hypoxia inducible transcription factors (HIFs). Poor perfusion makes tumors hypoxic and induces the HIFs, which promote cell survival. We previously showed that hypoxic breast cancer cells are tamoxifen-resistant, and that HIF-inhibition restored tamoxifen-sensitivity. We found that HIF-induced tamoxifen-resistance involve cross-talk with epithelial growth factor receptor (EGFR), which itself is linked to tamoxifen resistance. Contralateral breast cancer (CBC), i.e. development of a second breast cancer in the contralateral breast despite adjuvant tamoxifen treatment is in essence a human in vivo-model for tamoxifen-resistance that we explore here to find molecular pathways of tamoxifen-resistance.

Methods

We constructed a tissue-microarray including tumor-tissue from a large well-defined cohort of CBC-patients, a proportion of which got their second breast cancer despite ongoing adjuvant therapy. Using immunohistochemistry >500 patients were evaluable for HIF-1α and EGFR in both tumors, and correlations to treatment, patient outcome, prognostic and predictive factors were analyzed.

Results

We found an increased proportion of HIF-1α-positive tumors in tamoxifen-resistant (CBC during adjuvant tamoxifen) compared to naïve tumors (CBC without prior tamoxifen). Tumor HIF-1α-positivity correlated to increased breast cancer mortality, and negative prognostic factors including low age at diagnosis and ER-negativity. There was a covariance of HIF-1α- and EGFR-expression and also EGFR-expression correlated to poor prognosis.

Conclusions

The increased percentage of HIF-1α-positive tumors formed during adjuvant tamoxifen suggests a role for HIF-1α in escaping tamoxifen’s restraining effects on breast cancer. Implicating a potential benefit of HIF-inhibitors in targeting breast cancers resistant to endocrine therapy.

Klíčová slova:

Breast cancer – Cancer detection and diagnosis – Cancer treatment – Endocrine therapy – Hypoxia – Immunologic adjuvants – Medical hypoxia – Prognosis


Zdroje

1. Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 1999;17(5):1474–81. doi: 10.1200/JCO.1999.17.5.1474 10334533.

2. Early Breast Cancer Trialists' Collaborative G, Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84. Epub 2011/08/02. doi: 10.1016/S0140-6736(11)60993-8 21802721; PubMed Central PMCID: PMC3163848.

3. Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9(9):631–43. Epub 2009/08/25. doi: 10.1038/nrc2713 [pii] 19701242.

4. Sandberg ME, Hartman M, Klevebring D, Eloranta S, Ploner A, Hall P, et al. Prognostic implications of estrogen receptor pattern of both tumors in contralateral breast cancer. Breast cancer research and treatment. 2012;134(2):793–800. doi: 10.1007/s10549-012-2096-3 22622811.

5. Alkner S, Bendahl PO, Ferno M, Manjer J, Ryden L. Prediction of outcome after diagnosis of metachronous contralateral breast cancer. BMC Cancer. 2011;11:114. Epub 2011/04/01. doi: 10.1186/1471-2407-11-114 21450091; PubMed Central PMCID: PMC3080341.

6. Hartman M, Czene K, Reilly M, Adolfsson J, Bergh J, Adami HO, et al. Incidence and prognosis of synchronous and metachronous bilateral breast cancer. J Clin Oncol. 2007;25(27):4210–6. doi: 10.1200/JCO.2006.10.5056 17878475.

7. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(12):5510–4. doi: 10.1073/pnas.92.12.5510 7539918

8. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–34. Epub 2009/12/01. doi: 10.1038/onc.2009.441 19946328; PubMed Central PMCID: PMC2969168.

9. Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes & development. 1998;12(21):3320–4.

10. Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nature reviews. 2012;12(1):9–22. Epub 2011/12/16. doi: 10.1038/nrc3183 22169972; PubMed Central PMCID: PMC3401912.

11. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer metastasis reviews. 2007;26(2):225–39. doi: 10.1007/s10555-007-9055-1 17440684.

12. Helczynska K, Larsson AM, Holmquist Mengelbier L, Bridges E, Fredlund E, Borgquist S, et al. Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer research. 2008;68(22):9212–20. doi: 10.1158/0008-5472.CAN-08-1135 19010893.

13. Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, et al. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 2003;97(6):1573–81. doi: 10.1002/cncr.11246 12627523.

14. Wang W, He YF, Sun QK, Wang Y, Han XH, Peng DF, et al. Hypoxia-inducible factor 1alpha in breast cancer prognosis. Clinica chimica acta; international journal of clinical chemistry. 2014;428:32–7. doi: 10.1016/j.cca.2013.10.018 24482805.

15. Alam MW, Persson CU, Reinbothe S, Kazi JU, Ronnstrand L, Wigerup C, et al. HIF2alpha contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells. Oncotarget. 2016;7(10):11238–50. doi: 10.18632/oncotarget.7167 26849233; PubMed Central PMCID: PMC4905469.

16. Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast cancer research and treatment. 2009;114(2):263–75. doi: 10.1007/s10549-008-0011-8 18409071; PubMed Central PMCID: PMC2764248.

17. Bos R, van Diest PJ, de Jong JS, van der Groep P, van der Valk P, van der Wall E. Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology. 2005;46(1):31–6. doi: 10.1111/j.1365-2559.2005.02045.x 15656883.

18. Alkner S, Ehinger A, Bendahl PO, Ryden L, Ferno M. Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy. European journal of cancer. 2015;51(16):2304–13. doi: 10.1016/j.ejca.2015.07.016 26243193.

19. Alkner S, Bendahl PO, Ehinger A, Lovgren K, Ryden L, Ferno M. Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer. PloS one. 2016;11(3):e0150977. doi: 10.1371/journal.pone.0150977 26959415; PubMed Central PMCID: PMC4784945.

20. Briand P, Lykkesfeldt AE. Effect of estrogen and antiestrogen on the human breast cancer cell line MCF-7 adapted to growth at low serum concentration. Cancer research. 1984;44(3):1114–9. 6362856.

21. Lykkesfeldt AE, Larsen SS, Briand P. Human breast cancer cell lines resistant to pure anti-estrogens are sensitive to tamoxifen treatment. International journal of cancer. 1995;61(4):529–34. doi: 10.1002/ijc.2910610417 7759159.

22. Lykkesfeldt AE, Madsen MW, Briand P. Altered expression of estrogen-regulated genes in a tamoxifen-resistant and ICI 164,384 and ICI 182,780 sensitive human breast cancer cell line, MCF-7/TAMR-1. Cancer research. 1994;54(6):1587–95. 8137264.

23. Alkner S, Bendahl PO, Grabau D, Lovgren K, Stal O, Ryden L, et al. AIB1 is a predictive factor for tamoxifen response in premenopausal women. Ann Oncol. 2010;21(2):238–44. Epub 2009/07/25. doi: 10.1093/annonc/mdp293 19628566.

24. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206–23. doi: 10.1093/annonc/mdt303 23917950; PubMed Central PMCID: PMC3755334.

25. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-a to the von Hippel-Lindau ubiquitylation complex by o2-regulated prolyl hydroxylation. Science. 2001;292:468–72. doi: 10.1126/science.1059796 11292861

26. Generali D, Berruti A, Brizzi MP, Campo L, Bonardi S, Wigfield S, et al. Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. Clin Cancer Res. 2006;12(15):4562–8. doi: 10.1158/1078-0432.CCR-05-2690 16899602.

27. Bos R, Zhong H, Hanrahan CF, Mommers EC, Semenza GL, Pinedo HM, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001;93(4):309–14. doi: 10.1093/jnci/93.4.309 11181778.

28. Helczynska K, Kronblad A, Jögi A, Nilsson E, Beckman S, Landberg G, et al. Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer research. 2003;63(7):1441–4. 12670886.


Článek vyšel v časopise

PLOS One


2019 Číslo 12