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Open Access 01-05-2020 | Breast Cancer | Preclinical study

The solute carrier SLC7A8 is a marker of favourable prognosis in ER-positive low proliferative invasive breast cancer

Authors: Rokaya El Ansari, Lutfi Alfarsi, Madeleine L. Craze, Brendah K. Masisi, Ian O. Ellis, Emad A. Rakha, Andrew R. Green

Published in: Breast Cancer Research and Treatment | Issue 1/2020

Abstract

Purpose

Breast cancer (BC) is a heterogeneous disease consisting of various subtypes, with different prognostic and therapeutic outcomes. The amino acid transporter, SLC7A8, is overexpressed in oestrogen receptor-positive BC. However, the consequence of this overexpression, in terms of disease prognosis, is still obscure. This study aimed to evaluate the biological and prognostic value of SLC7A8 in BC with emphasis on the intrinsic molecular subtypes.

Methods

SLC7A8 was assessed at the genomic, using METABRIC data (n = 1980), and proteomic, using immunohistochemistry and TMA (n = 1562), levels in well-characterised primary BC cohorts. SLC7A8 expression was examined with clinicopathological parameters, molecular subtypes, and patient outcome.

Results

SLC7A8 mRNA and SLC7A8 protein expression were strongly associated with good prognostic features, including small tumour size, low tumour grade, and good Nottingham Prognostic Index (NPI) (all P < 0.05). Expression of SLC7A8 mRNA was higher in luminal tumours compared to other subtypes (P < 0.001). High expression of SLC7A8 mRNA and SLC7A8 protein was associated with good patient outcome (P ≤ 0.001) but only in the low proliferative ER+/luminal A tumours (P = 0.01). In multivariate analysis, SLC7A8 mRNA and SLC7A8 protein were independent factors for longer breast cancer specific survival (P = 0.01 and P = 0.03), respectively.

Conclusion

SLC7A8 appears to play a role in BC and is a marker for favourable prognosis in the most predominant, ER+ low proliferative/luminal A, BC subtype. Functional assessment is necessary to reveal the specific role played by SLC7A8 in ER+ BC.

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Bond P (2016) Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance. J Int Soc Sports Nutr 13:8. https://doi.org/10.1186/s12970-016-0118-y CrossRefPubMedPubMedCentral

Bar-Peled L, Sabatini DM (2014) Regulation of mTORC1 by amino acids. Trends Cell Biol 24(7):400–406. https://doi.org/10.1016/j.tcb.2014.03.003 CrossRefPubMedPubMedCentral

Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239):762–765. https://doi.org/10.1038/nature07823 CrossRefPubMedPubMedCentral

Shennan DB, Thomson J, Gow IF, Travers MT, Barber MC (2004) L-leucine transport in human breast cancer cells (MCF-7 and MDA-MB-231): kinetics, regulation by estrogen and molecular identity of the transporter. Biochem Biophys Acta 1664(2):206–216. https://doi.org/10.1016/j.bbamem.2004.05.008 CrossRefPubMed

Hellsten SV, Tripathi R, Ceder MM, Fredriksson R (2018) Nutritional stress induced by amino acid starvation results in changes for Slc38 transporters in immortalized hypothalamic neuronal cells and primary cortex cells. Front Mol Biosci 5:45. https://doi.org/10.3389/fmolb.2018.00045 CrossRefPubMedPubMedCentral

Bhutia YD (1863) Ganapathy V (2016) Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochem Biophys Acta 10:2531–2539. https://doi.org/10.1016/j.bbamcr.2015.12.017 CrossRef

Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem 273(37):23629–23632CrossRefPubMed

Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, Lloberas J, Zorzano A, Palacin M (1999) Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem 274(28):19738–19744. https://doi.org/10.1074/jbc.274.28.19738 CrossRefPubMed

Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kuhn LC (1999) LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem 274(49):34948–34954. https://doi.org/10.1074/jbc.274.49.34948 CrossRefPubMed

10.

Kobayashi H, Ishii Y, Takayama T (2005) Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma. J Surg Oncol 90(4):233–238. https://doi.org/10.1002/jso.20257 CrossRefPubMed

11.

Yoon JH, Kim IJ, Kim H, Kim HJ, Jeong MJ, Ahn SG, Kim SA, Lee CH, Choi BK, Kim JK, Jung KY, Lee S, Kanai Y, Endou H, Kim DK (2005) Amino acid transport system L is differently expressed in human normal oral keratinocytes and human oral cancer cells. Cancer Lett 222(2):237–245. https://doi.org/10.1016/j.canlet.2004.09.040 CrossRefPubMed

12.

Nakanishi K, Matsuo H, Kanai Y, Endou H, Hiroi S, Tominaga S, Mukai M, Ikeda E, Ozeki Y, Aida S, Kawai T (2006) LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Virchows Arch 448(2):142–150. https://doi.org/10.1007/s00428-005-0063-7 CrossRefPubMed

13.

Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T (2012) Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci 103(2):382–389. https://doi.org/10.1111/j.1349-7006.2011.02151.x CrossRefPubMed

14.

El Ansari R, Craze ML, Miligy I, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR (2018) The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours. Breast Cancer Res 20(1):21. https://doi.org/10.1186/s13058-018-0946-6 CrossRefPubMedPubMedCentral

15.

Thakkar A, Raj H, Ravishankar MB, Balakrishnan A, Padigaru M (2015) High expression of three-gene signature improves prediction of relapse-free survival in estrogen receptor-positive and node-positive breast tumors. Biomark insights 10:103–112. https://doi.org/10.4137/bmi.S30559 CrossRefPubMedPubMedCentral

16.

Luo X, Yin P, Reierstad S, Ishikawa H, Lin Z, Pavone ME, Zhao H, Marsh EE, Bulun SE (2009) Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells. J Clin Endocrinol Metab 94(11):4533–4539. https://doi.org/10.1210/jc.2009-1286 CrossRefPubMedPubMedCentral

17.

Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352. https://doi.org/10.1038/nature10983 CrossRefPubMedPubMedCentral

18.

Craze ML, Cheung H, Jewa N, Coimbra ND, Soria D, El-Ansari R, Aleskandarany MA, Cheng KW, Diez-Rodriguez M, Nolan CC (2017) MYC regulation of Glutamine-Proline regulatory axis is key in Luminal B breast cancer. Br J Cancer 118(2):258–265CrossRefPubMedPubMedCentral

19.

Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350. https://doi.org/10.1002/ijc.21004 CrossRefPubMed

20.

McCarty KS Jr, McCarty KS Sr (1984) Histochemical approaches to steroid receptor analyses. Semin Diagn Pathol 1(4):297–308PubMed

21.

Craze ML, El-Ansari R, Aleskandarany MA, Cheng KW, Alfarsi L, Masisi B, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA, Green AR (2019) Glutamate dehydrogenase (GLUD1) expression in breast cancer. Breast Cancer Res Treat 174(1):79–91. https://doi.org/10.1007/s10549-018-5060-z CrossRefPubMed

22.

Green AR, Aleskandarany MA, Agarwal D, Elsheikh S, Nolan CC, Diez-Rodriguez M, Macmillan RD, Ball GR, Caldas C, Madhusudan S, Ellis IO, Rakha EA (2016) MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours. Br J Cancer 114(8):917–928. https://doi.org/10.1038/bjc.2016.46 CrossRefPubMedPubMedCentral

23.

Elston CW, Ellis IO (2002) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. C. W. Elston & I. O. Ellis. Histopathology 1991; 19; 403–410. Histopathology 41 (3a):151–152, discussion 152–153

24.

Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F (2015) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26(Suppl 5):v8–30. https://doi.org/10.1093/annonc/mdv298 CrossRefPubMed

25.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93(4):387–391. https://doi.org/10.1038/sj.bjc.6602678 CrossRefPubMedPubMedCentral

26.

Pochini L, Scalise M, Galluccio M, Indiveri C (2014) Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health. Front Chem 2:61. https://doi.org/10.3389/fchem.2014.00061 CrossRefPubMedPubMedCentral

27.

El Ansari R, McIntyre A, Craze ML, Ellis IO, Rakha EA, Green AR (2018) Altered glutamine metabolism in breast cancer; subtype dependencies and alternative adaptations. Histopathology 72(2):183–190. https://doi.org/10.1111/his.13334 CrossRefPubMed

28.

Cha YJ, Kim ES, Koo JS (2018) Amino acid transporters and glutamine metabolism in breast cancer. Int J Mol Sci 19(3):907. https://doi.org/10.3390/ijms19030907 CrossRefPubMedCentral

29.

Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. https://doi.org/10.1038/35021093 CrossRefPubMed

30.

Rakha EA, El-Sayed ME, Green AR, Paish EC, Powe DG, Gee J, Nicholson RI, Lee AH, Robertson JF, Ellis IO (2007) Biologic and clinical characteristics of breast cancer with single hormone receptor positive phenotype. J Clin Oncol 25(30):4772–4778. https://doi.org/10.1200/jco.2007.12.2747 CrossRefPubMed

31.

Dawson SJ, Rueda OM, Aparicio S, Caldas C (2013) A new genome-driven integrated classification of breast cancer and its implications. EMBO J 32(5):617–628. https://doi.org/10.1038/emboj.2013.19 CrossRefPubMedPubMedCentral

32.

Ring BZ, Seitz RS, Beck R, Shasteen WJ, Tarr SM, Cheang MC, Yoder BJ, Budd GT, Nielsen TO, Hicks DG, Estopinal NC, Ross DT (2006) Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer. J Clin Oncol 24(19):3039–3047. https://doi.org/10.1200/jco.2006.05.6564 CrossRefPubMed

33.

Kanaan YM, Sampey BP, Beyene D, Esnakula AK, Naab TJ, Ricks-Santi LJ, Dasi S, Day A, Blackman KW, Frederick W, Copeland RL Sr, Gabrielson E, Dewitty RL Jr (2014) Metabolic profile of triple-negative breast cancer in African-American women reveals potential biomarkers of aggressive disease. Cancer Genomics Proteom 11(6):279–294

34.

Cao MD, Lamichhane S, Lundgren S, Bofin A, Fjosne H, Giskeodegard GF, Bathen TF (2014) Metabolic characterization of triple negative breast cancer. BMC Cancer 14:941. https://doi.org/10.1186/1471-2407-14-941 CrossRefPubMedPubMedCentral

35.

Wang Q, Holst J (2015) L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am J Cancer Res 5(4):1281–1294PubMedPubMedCentral

36.

Wang Q, Beaumont KA, Otte NJ, Font J, Bailey CG, van Geldermalsen M, Sharp DM, Tiffen JC, Ryan RM, Jormakka M, Haass NK, Rasko JE, Holst J (2014) Targeting glutamine transport to suppress melanoma cell growth. Int J Cancer 135(5):1060–1071. https://doi.org/10.1002/ijc.28749 CrossRefPubMed

37.

Shennan DB, Thomson J, Barber MC, Travers MT (2003) Functional and molecular characteristics of system L in human breast cancer cells. Biochem Biophys Acta 1611(1–2):81–90. https://doi.org/10.1016/s0005-2736(03)00028-2 CrossRefPubMed

38.

Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA 107(16):7461–7466. https://doi.org/10.1073/pnas.1002459107 CrossRefPubMedPubMedCentral

39.

Bermudez-Soto MJ, Larrosa M, Garcia-Cantalejo JM, Espin JC, Tomas-Barberan FA, Garcia-Conesa MT (2007) Up-regulation of tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 in human colon cancer Caco-2 cells following repetitive exposure to dietary levels of a polyphenol-rich chokeberry juice. J Nutr Biochem 18(4):259–271. https://doi.org/10.1016/j.jnutbio.2006.05.003 CrossRefPubMed

40.

Meier C, Ristic Z, Klauser S, Verrey F (2002) Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J 21(4):580–589. https://doi.org/10.1093/emboj/21.4.580 CrossRefPubMedPubMedCentral

41.

Liu J, Zhang C, Lin M, Zhu W, Liang Y, Hong X, Zhao Y, Young KH, Hu W, Feng Z (2014) Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma. Oncotarget 5(9):2635–2647. https://doi.org/10.18632/oncotarget.1862 CrossRefPubMedPubMedCentral

42.

del Amo EM, Urtti A, Yliperttula M (2008) Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. Eur J Pharm Sci 35(3):161–174. https://doi.org/10.1016/j.ejps.2008.06.015 CrossRefPubMed

43.

van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O'Toole SA, Rasko JE, Holst J (2016) ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene 35(24):3201–3208. https://doi.org/10.1038/onc.2015.381 CrossRefPubMed

Title: The solute carrier SLC7A8 is a marker of favourable prognosis in ER-positive low proliferative invasive breast cancer
Authors: Rokaya El Ansari
Lutfi Alfarsi
Madeleine L. Craze
Brendah K. Masisi
Ian O. Ellis
Emad A. Rakha
Andrew R. Green
Publication date: 01-05-2020
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 1/2020
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05586-6

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