Serine synthesis influences tamoxifen response in ER+ human breast carcinoma

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, Kentucky, USA
  • 2 James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA

Correspondence should be addressed to B F Clem: brian.clem@louisville.edu

(S Metcalf is now at Indiana University School of Medicine, Indiana University, Bloomington, Indiana, USA)

*(T Kruer is now at Moffitt Cancer Center, University of South Florida, Tampa, Florida, USA)

Restricted access

Estrogen receptor-positive breast cancer (ER+ BC) is the most common form of breast carcinoma accounting for approximately 70% of all diagnoses. Although ER-targeted therapies have improved survival outcomes for this BC subtype, a significant proportion of patients will ultimately develop resistance to these clinical interventions, resulting in disease recurrence. Phosphoserine aminotransferase 1 (PSAT1), an enzyme within the serine synthetic pathway (SSP), has been previously implicated in endocrine resistance. Therefore, we determined whether expression of SSP enzymes, PSAT1 or phosphoglycerate dehydrogenase (PHGDH), affects the response of ER+ BC to 4-hydroxytamoxifen (4-OHT) treatment. To investigate a clinical correlation between PSAT1, PHGDH, and endocrine resistance, we examined microarray data from ER+ patients who received tamoxifen as the sole endocrine therapy. We confirmed that higher PSAT1 and PHGDH expression correlates negatively with poorer outcomes in tamoxifen-treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis were elevated in tamoxifen-resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of either PSAT1 or PHGDH in each cell type. Overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition on cell proliferation. Conversely, silencing of either PSAT1 or PHGDH resulted in greater sensitivity to 4-OHT treatment in LCC9 tamoxifen-resistant cells. Likewise, the combination of a PHGDH inhibitor with 4-OHT decreased LCC9 cell proliferation. Collectively, these results suggest that overexpression of serine synthetic pathway enzymes contribute to tamoxifen resistance in ER+ BC, which can be targeted as a novel combinatorial treatment option.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 261 261 214
Full Text Views 83 83 76
PDF Downloads 18 18 15
  • Ali S, Rasool M, Chaoudhry H, N Pushparaj P, Jha P, Hafiz A, Mahfooz M, Abdus Sami G, Azhar Kamal M & Bashir S et al. 2016 Molecular mechanisms and mode of tamoxifen resistance in breast cancer. Bioinformation 12 135139. (https://doi.org/10.6026/97320630012135)

    • Search Google Scholar
    • Export Citation
  • Andres SA & Wittliff JL 2012 Co-expression of genes with estrogen receptor-alpha and progesterone receptor in human breast carcinoma tissue. Hormone Molecular Biology and Clinical Investigation 12 3773 90. (https://doi.org/10.1515/hmbci-2012-0025)

    • Search Google Scholar
    • Export Citation
  • Andres SA, Brock GN & Wittliff JL 2013 Interrogating differences in expression of targeted gene sets to predict breast cancer outcome. BMC Cancer 13 326. (https://doi.org/10.1186/1471-2407-13-326)

    • Search Google Scholar
    • Export Citation
  • Astruc ME, Chabret C, Bali P, Gagne D & Pons M 1995 Prolonged treatment of breast cancer cells with antiestrogens increases the activating protein-1-mediated response: involvement of the estrogen receptor. Endocrinology 136 8248 32. (https://doi.org/10.1210/endo.136.3.7867590)

    • Search Google Scholar
    • Export Citation
  • Bai Z & Gust R 2009 Breast cancer, estrogen receptor and ligands. Archiv Der Pharmazie 342 1331 49. (https://doi.org/10.1002/ardp.200800174)

    • Search Google Scholar
    • Export Citation
  • Bronzert DA, Greene GL & Lippman ME 1985 Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018. Endocrinology 117 14091417. (https://doi.org/10.1210/endo-117-4-1409)

    • Search Google Scholar
    • Export Citation
  • Brunner N, Boysen B, Jirus S, Skaar TC, Holst-Hansen C, Lippman J, Frandsen T, Spang-Thomsen M, Fuqua SA & Clarke R 1997 MCF7/LCC9: an antiestrogen-resistant MCF-7 variant in which acquired resistance to the steroidal antiestrogen ICI 182,780 confers an early cross-resistance to the nonsteroidal antiestrogen tamoxifen. Cancer Research 57 348634 93.

    • Search Google Scholar
    • Export Citation
  • Chen Z, Wang Y, Warden C & Chen S 2015 Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. Journal of Steroid Biochemistry and Molecular Biology 149 1181 27. (https://doi.org/10.1016/j.jsbmb.2015.02.004)

    • Search Google Scholar
    • Export Citation
  • Clarke R, Tyson JJ & Dixon JM 2015 Endocrine resistance in breast cancer – an overview and update. Molecular and Cellular Endocrinology 418 2202 34. (https://doi.org/10.1016/j.mce.2015.09.035)

    • Search Google Scholar
    • Export Citation
  • De Marchi T, Foekens JA, Umar A & Martens JW 2016 Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer. Drug Discovery Today 21 1181118 8. (https://doi.org/10.1016/j.drudis.2016.05.012)

    • Search Google Scholar
    • Export Citation
  • De Marchi T, Timmermans MA, Sieuwerts AM, Smid M, Look MP, Grebenchtchikov N, Sweep FCGJ, Smits JG, Magdolen V & Van Deurzen CHM et al. 2017 Phosphoserine aminotransferase 1 is associated to poor outcome on tamoxifen therapy in recurrent breast cancer. Scientific Reports 7 2099. (https://doi.org/10.1038/s41598-017-02296-w)

    • Search Google Scholar
    • Export Citation
  • Dixon JM 2014 Endocrine resistance in breast cancer. New Journal of Science 2014 127. (https://doi.org/10.1155/2014/390618)

  • Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A & Colleoni M et al. 2010 Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. Journal of Clinical Oncology 28 5095 18. (https://doi.org/10.1200/JCO.2009.23.1274)

    • Search Google Scholar
    • Export Citation
  • Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 2005 Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365 16871 717. (https://doi.org/10.1016/S0140-6736(0566544-0)

    • Search Google Scholar
    • Export Citation
  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C & Parkin DM 2010 Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer 127 28932 917. (https://doi.org/10.1002/ijc.25516)

    • Search Google Scholar
    • Export Citation
  • Fisher B, Redmond C, Brown A, Wolmark N, Wittliff J, Fisher ER, Plotkin D, Bowman D, Sachs S & Wolter J et al. 1981 Treatment of primary breast cancer with chemotherapy and tamoxifen. New England Journal of Medicine 305 16. (https://doi.org/10.1056/NEJM198107023050101)

    • Search Google Scholar
    • Export Citation
  • Fisher B, Redmond C, Brown A, Wickerham DL, Wolmark N, Allegra J, Escher G, Lippman M, Savlov E & Wittliff J 1983 Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. Journal of Clinical Oncology 1 2272 41. (https://doi.org/10.1200/JCO.1983.1.4.227)

    • Search Google Scholar
    • Export Citation
  • Gao S, Ge A, Xu S, You Z, Ning S, Zhao Y & Pang D 2017 PSAT1 is regulated by ATF4 and enhances cell proliferation via the GSK3beta/beta-catenin/cyclin D1 signaling pathway in ER-negative breast cancer. Journal of Experimental and Clinical Cancer Research 36 179. (https://doi.org/10.1186/s13046-017-0648-4)

    • Search Google Scholar
    • Export Citation
  • Gaudet HM, Cheng SB, Christensen EM & Filardo EJ 2015 The G-protein coupled estrogen receptor, GPER: the inside and inside-out story. Molecular and Cellular Endocrinology 418 2072 19. (https://doi.org/10.1016/j.mce.2015.07.016)

    • Search Google Scholar
    • Export Citation
  • Girault I, Bieche I & Lidereau R 2006 Role of estrogen receptor alpha transcriptional coregulators in tamoxifen resistance in breast cancer. Maturitas 54 3423 51. (https://doi.org/10.1016/j.maturitas.2006.06.003)

    • Search Google Scholar
    • Export Citation
  • Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q & Szallasi Z 2010 An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Research and Treatment 123 7257 31. (https://doi.org/10.1007/s10549-009-0674-9)

    • Search Google Scholar
    • Export Citation
  • Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS & Hayes M et al. 2010 American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Journal of Clinical Oncology 28 278427 95. (https://doi.org/10.1200/JCO.2009.25.6529)

    • Search Google Scholar
    • Export Citation
  • Lane AN, Tan J, Wang Y, Yan J, Higashi RM & Fan TW 2017 Probing the metabolic phenotype of breast cancer cells by multiple tracer stable isotope resolved metabolomics. Metabolic Engineering 43 125136. (https://doi.org/10.1016/j.ymben.2017.01.010)

    • Search Google Scholar
    • Export Citation
  • Liao KM, Chao TB, Tian YF, Lin CY, Lee SW, Chuang HY, Chan TC, Chen TJ, Hsing CH & Sheu MJ et al. 2016 Overexpression of the PSAT1 gene in nasopharyngeal carcinoma is an indicator of poor prognosis. Journal of Cancer 7 108810 94. (https://doi.org/10.7150/jca.15258)

    • Search Google Scholar
    • Export Citation
  • Liu B, Jia Y, Cao Y, Wu S, Jiang H, Sun X, Ma J, Yin X, Mao A & Shang M 2016 Overexpression of phosphoserine aminotransferase 1 (PSAT1) predicts poor prognosis and associates with tumor progression in human esophageal squamous cell carcinoma. Cellular Physiology and Biochemistry 39 395406. (https://doi.org/10.1159/000445633)

    • Search Google Scholar
    • Export Citation
  • Martens JW, Nimmrich I, Koenig T, Look MP, Harbeck N, Model F, Kluth A, Bolt-De Vries J, Sieuwerts AM & Portengen H et al. 2005 Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer. Cancer Research 65 410141 17. (https://doi.org/10.1158/0008-5472.CAN-05-0064)

    • Search Google Scholar
    • Export Citation
  • Mattaini KR, Sullivan MR & Vander Heiden MG 2016 The importance of serine metabolism in cancer. Journal of Cell Biology 214 2492 57. (https://doi.org/10.1083/jcb.201604085)

    • Search Google Scholar
    • Export Citation
  • McNeil CM, Sergio CM, Anderson LR, Inman CK, Eggleton SA, Murphy NC, Millar EK, Crea P, Kench JG & Alles MC et al. 2006 c-Myc overexpression and endocrine resistance in breast cancer. Journal of Steroid Biochemistry and Molecular Biology 102 1471 55. (https://doi.org/10.1016/j.jsbmb.2006.09.028)

    • Search Google Scholar
    • Export Citation
  • Mihaly Z, Kormos M, Lanczky A, Dank M, Budczies J, Szasz MA & Gyorffy B 2013 A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer. Breast Cancer Research and Treatment 140 2192 32. (https://doi.org/10.1007/s10549-013-2622-y)

    • Search Google Scholar
    • Export Citation
  • Mullarky E, Lucki NC, Beheshti Zavareh R, Anglin JL, Gomes AP, Nicolay BN, Wong JC, Christen S, Takahashi H & Singh PK et al. 2016 Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. PNAS 113 177817 83. (https://doi.org/10.1073/pnas.1521548113)

    • Search Google Scholar
    • Export Citation
  • Newman AC & Maddocks ODK 2017 Serine and functional metabolites in cancer. Trends in Cell Biology 27 645657. (https://doi.org/10.1016/j.tcb.2017.05.001)

    • Search Google Scholar
    • Export Citation
  • Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJ, Possemato R, Chen WW, Sullivan LB & Fiske BP et al. 2016 A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nature Chemical Biology 12 45245 8. (https://doi.org/10.1038/nchembio.2070)

    • Search Google Scholar
    • Export Citation
  • Perou CM, Sorlie T, Eisen MB, Van De Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H & Akslen LA et al. 2000 Molecular portraits of human breast tumours. Nature 406 7477 52. (https://doi.org/10.1038/35021093)

    • Search Google Scholar
    • Export Citation
  • Robertson JF 2001 ICI 182,780 (fulvestrant) – the first oestrogen receptor down-regulator – current clinical data. British Journal of Cancer 85 (Supplement 2) 111 4. (https://doi.org/10.1054/bjoc.2001.1982)

    • Search Google Scholar
    • Export Citation
  • Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M & Wagner P et al. 2005 Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clinical Cancer Research 11 567856 85. (https://doi.org/10.1158/1078-0432.CCR-04-2421)

    • Search Google Scholar
    • Export Citation
  • Sporn MB & Lippman SM 2003 Agents for chemoprevention and their mechanism of action. In Holland-Frei Cancer Medicine, 6th ed. Eds Kufe DW, Pollock RE, Weichselbaum RR, et al. Hamilton (ON): BC Decker.

    • Search Google Scholar
    • Export Citation
  • Stone A, Valdes-Mora F, Gee JM, Farrow L, Mcclelland RA, Fiegl H, Dutkowski C, Mccloy RA, Sutherland RL & Musgrove EA et al. 2012 Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer. PLoS ONE 7 e40466. (https://doi.org/10.1371/journal.pone.0040466)

    • Search Google Scholar
    • Export Citation
  • Sun L, Song L, Wan Q, Wu G, Li X, Wang Y, Wang J, Liu Z, Zhong X & He X et al. 2015 cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Research 25 42944 4. (https://doi.org/10.1038/cr.2015.33)

    • Search Google Scholar
    • Export Citation
  • Sun C, Zhang X, Chen Y, Jia Q, Yang J & Shu Y 2018 MicroRNA-365 suppresses cell growth and invasion in esophageal squamous cell carcinoma by modulating phosphoserine aminotransferase 1. Cancer Management and Research 10 45814590. (https://doi.org/10.2147/CMAR.S157858)

    • Search Google Scholar
    • Export Citation
  • Van Agthoven T, Sieuwerts AM, Veldscholte J, Meijer-Van Gelder ME, Smid M, Brinkman A, Den Dekker AT, Leroy IM, Van Ijcken WF & Sleijfer S et al. 2009 CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer. British Journal of Cancer 101 18241832. (https://doi.org/10.1038/sj.bjc.6605423)

    • Search Google Scholar
    • Export Citation
  • Wang Q, Liberti MV, Liu P, Deng X, Liu Y, Locasale JW & Lai L 2017 Rational design of selective allosteric inhibitors of PHGDH and serine synthesis with anti-tumor activity. Cell Chemical Biology 24 5565. (https://doi.org/10.1016/j.chembiol.2016.11.013)

    • Search Google Scholar
    • Export Citation
  • Wittliff J 2010 Laser capture microdissection and its use in genomics and proteomics. In Reliable Lab Solutions: Techniques in Confocal Microscopy, pp. 463477. Boston: Elsevier.

    • Search Google Scholar
    • Export Citation
  • Wittliff J, Pasic R & Bland K 1998 Steroid and peptide hormone receptors: methods, quality control and clinical use. In Breast: Comprehensive Management of Benign and Malignant Diseases, pp. 458498. Philadelphia, PA: WB Saunders Company.

    • Search Google Scholar
    • Export Citation
  • Wittliff JL, Kruer TL, Andres SA & Smolenkova I 2008 Molecular signatures of estrogen receptor-associated genes in breast cancer predict clinical outcome. Advances in Experimental Medicine and Biology 617 3493 57. (https://doi.org/10.1007/978-0-387-69080-3_33)

    • Search Google Scholar
    • Export Citation
  • Yan S, Jiang H, Fang S, Yin F, Wang Z, Jia Y, Sun X, Wu S, Jiang T & Mao A 2015 MicroRNA-340 inhibits esophageal cancer cell growth and invasion by targeting phosphoserine aminotransferase 1. Cellular Physiology and Biochemistry 37 375386. (https://doi.org/10.1159/000430361)

    • Search Google Scholar
    • Export Citation
  • Yang Y, Wu J, Cai J, He Z, Yuan J, Zhu X, Li Y, Li M & Guan H 2015 PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells. International Journal of Cancer 136 E39E 50. (https://doi.org/10.1002/ijc.29150)

    • Search Google Scholar
    • Export Citation
  • Yip CH & Rhodes A 2014 Estrogen and progesterone receptors in breast cancer. Future Oncology 10 22932 301. (https://doi.org/10.2217/fon.14.110)

    • Search Google Scholar
    • Export Citation