SLC7A5 is linked to increased expression of genes related to proliferation and hypoxia in estrogen‑receptor‑positive breast cancer

Törnroos,Rasmus; Tina,Elisabet; Göthlin Eremo,Anna

doi:10.3892/or.2021.8228

SLC7A5 is linked to increased expression of genes related to proliferation and hypoxia in estrogen‑receptor‑positive breast cancer

Authors:
- Rasmus Törnroos
- Elisabet Tina
- Anna Göthlin Eremo
View Affiliations

Affiliations: School of Medical Sciences, Faculty of Medicine and Health, Örebro University, SE-70185 Örebro, Sweden
Published online on: November 16, 2021 https://doi.org/10.3892/or.2021.8228
Article Number: 17
Copyright: © Törnroos et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The amino acid transporter named solute carrier family 7 member 5 (SLC7A5) is suggested to play a part in altered cell metabolism and proliferative signaling and has been reported to be overexpressed in various types of cancer, including breast cancer. Estrogen‑receptor‑positive (ER⁺) breast cancers constitute the most common type of breast malignancies and are often treated with anti‑estrogenic therapies. In this group of patients, endocrine resistance is a challenging problem that could lead to recurrent disease. To overcome this, additional prognostic biomarkers are needed. The present study aimed therefore to determine whether SLC7A5 may be considered as a possible prognostic marker in ER⁺ breast cancer and to investigate its relation with certain cancer‑related genes. We used a local breast cancer cohort (n=154) and immunohistochemistry to analyze the expression of SLC7A5 in association with clinicopathological characteristics and patient outcome. In addition, gene expression analysis was performed on 80 of these tumors. Furthermore, the METABRIC dataset was used for correlation analyses between expression of SLC7A5 and several genes related to breast cancer biology. The results demonstrated that overexpression of SLC7A5 was significantly associated with histopathological grade in patients with breast cancer, and that SLC7A5 mRNA expression was positively correlated with the expression of marker of proliferation Ki‑67 and hypoxia inducible factor 1 subunit alpha. Overexpression of SLC7A5 may therefore play a role in the biology of endocrinologically‑driven disease. However, when further assessing SLC7A5 using the METABRIC dataset, SLC7A5 mRNA expression level was more significantly increased in ER‑ subgroups compared with ER⁺ disease. All breast cancer subtypes included, SLC7A5 mRNA expression was correlated with a higher number of cancer‑related genes than in estrogen receptor positive tumors alone. The present study suggested that SLC7A5 expression may be of importance for breast cancer cell proliferation and survival. In order to further establish the biological and clinical role of SLC7A5 in breast cancer, further investigation using different breast cancer subgroups is required.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, Senn HJ, Albain KS, André F, Bergh J, et al Panel members, : 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. 24:2206–2223. 2013. View Article : Google Scholar : PubMed/NCBI
3	Harvey JM, Clark GM, Osborne CK and Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 17:1474–1481. 1999. View Article : Google Scholar : PubMed/NCBI
4	Duffy MJ, Harbeck N, Nap M, Molina R, Nicolini A, Senkus E and Cardoso F: Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer. 75:284–298. 2017. View Article : Google Scholar : PubMed/NCBI
5	El Sayed R, El Jamal L, El Iskandarani S, Kort J, Abdel Salam M and Assi H: Endocrine and targeted therapy for hormone-receptor-positive, HER2-negative advanced breast cancer: Insights to sequencing treatment and overcoming resistance based on clinical trials. Front Oncol. 9:5102019. View Article : Google Scholar : PubMed/NCBI
6	Häfliger P and Charles RP: The L-type amino acid transporter LAT1 - An emerging target in cancer. Int J Mol Sci. 20:24282019. View Article : Google Scholar : PubMed/NCBI
7	Scalise M, Galluccio M, Console L, Pochini L and Indiveri C: The human SLC7A5 (LAT1): The intriguing histidine/large neutral amino acid transporter and its relevance to human health. Front Chem. 6:2432018. View Article : Google Scholar : PubMed/NCBI
8	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
9	Elorza A, Soro-Arnáiz I, Meléndez-Rodríguez F, Rodríguez-Vaello V, Marsboom G, de Cárcer G, Acosta-Iborra B, Albacete-Albacete L, Ordóñez A, Serrano-Oviedo L, et al: HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell. 48:681–691. 2012. View Article : Google Scholar : PubMed/NCBI
10	Gatenby RA, Smallbone K, Maini PK, Rose F, Averill J, Nagle RB, Worrall L and Gillies RJ: Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer. 97:646–653. 2007. View Article : Google Scholar : PubMed/NCBI
11	Salisbury TB and Arthur S: The regulation and function of the L-type amino acid transporter 1 (LAT1) in cancer. Int J Mol Sci. 19:23732018. View Article : Google Scholar : PubMed/NCBI
12	Adamaki M: Cancer and the cellular response to hypoxia. Pediatr Ther. S1:0022012.
13	Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutté E, Massard PA, de la Ballina LR, Endou H, Wempe MF, et al: Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res. 76:4481–4492. 2016. View Article : Google Scholar : PubMed/NCBI
14	Göthlin Eremo A, Lagergren K, Othman L, Montgomery S, Andersson G and Tina E: Evaluation of SPP1/osteopontin expression as predictor of recurrence in tamoxifen treated breast cancer. Sci Rep. 10:14512020. View Article : Google Scholar : PubMed/NCBI
15	Tina E, Prosén S, Lennholm S, Gasparyan G, Lindberg M and Göthlin Eremo A: Expression profile of the amino acid transporters SLC7A5, SLC7A7, SLC7A8 and the enzyme TDO2 in basal cell carcinoma. Br J Dermatol. 180:130–140. 2019. View Article : Google Scholar : PubMed/NCBI
16	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
17	Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl1. 2013. View Article : Google Scholar : PubMed/NCBI
18	Curtis C, Shah SP, Chin S-F, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, et al METABRIC Group, : The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 486:346–352. 2012. View Article : Google Scholar : PubMed/NCBI
19	Rondón-Lagos M, Villegas VE, Rangel N, Sánchez MC and Zaphiropoulos PG: Tamoxifen resistance: Emerging molecular targets. Int J Mol Sci. 17:13572016. View Article : Google Scholar : PubMed/NCBI
20	Mihály Z, Kormos M, Lánczky A, Dank M, Budczies J, Szász MA and Győrffy B: A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer. Breast Cancer Res Treat. 140:219–232. 2013. View Article : Google Scholar : PubMed/NCBI
21	El Ansari R, Craze ML, Miligy I, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA and Green AR: 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. 20:212018. View Article : Google Scholar : PubMed/NCBI
22	Bodoor K, Almomani R, Alqudah M, Haddad Y and Samouri W: LAT1 (SLC7A5) overexpression in negative Her2 group of breast cancer: A potential therapy target. Asian Pac J Cancer Prev. 21:1453–1458. 2020. View Article : Google Scholar : PubMed/NCBI
23	Guan Q, Song X, Zhang Z, Zhang Y, Chen Y and Li J: Identification of tamoxifen-resistant breast cancer cell lines and drug response signature. Front Mol Biosci. 7:5640052020. View Article : Google Scholar : PubMed/NCBI
24	Bartlett JM, Thomas J, Ross DT, Seitz RS, Ring BZ, Beck RA, Pedersen HC, Munro A, Kunkler IH, Campbell FM, et al: Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy. Breast Cancer Res. 12:R472010. View Article : Google Scholar : PubMed/NCBI
25	Yan R, Zhao X, Lei J and Zhou Q: Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex. Nature. 568:127–130. 2019. View Article : Google Scholar : PubMed/NCBI
26	Alfarsi LH, El-Ansari R, Craze ML, Masisi BK, Mohammed OJ, Ellis IO, Rakha EA and Green AR: Co-expression effect of SLC7A5/SLC3A2 to predict response to endocrine therapy in oestrogen-receptor-positive breast cancer. Int J Mol Sci. 21:14072020. View Article : Google Scholar : PubMed/NCBI
27	El-Ansari R, Craze ML, Alfarsi L, Soria D, Diez-Rodriguez M, Nolan CC, Ellis IO, Rakha EA and Green AR: The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER⁺ breast cancer. Breast Cancer Res Treat. 175:27–38. 2019. View Article : Google Scholar : PubMed/NCBI
28	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
29	Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T, Kanai Y, et al: l-type amino acid transporter 1 and CD98 expression in primary and metastatic sites of human neoplasms. Cancer Sci. 99:2380–2386. 2008. View Article : Google Scholar : PubMed/NCBI
30	Semenza GL: HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985). 88:1474–1480. 2000. View Article : Google Scholar : PubMed/NCBI
31	Rathmell WK and Chen S: VHL inactivation in renal cell carcinoma: Implications for diagnosis, prognosis and treatment. Expert Rev Anticancer Ther. 8:63–73. 2008. View Article : Google Scholar : PubMed/NCBI
32	Lock FE, McDonald PC, Lou Y, Serrano I, Chafe SC, Ostlund C, Aparicio S, Winum JY, Supuran CT and Dedhar S: Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene. 32:5210–5219. 2013. View Article : Google Scholar : PubMed/NCBI
33	Valvona CJ, Fillmore HL, Nunn PB and Pilkington GJ: The regulation and function of lactate dehydrogenase A: Therapeutic potential in brain tumor. Brain Pathol. 26:3–17. 2016. View Article : Google Scholar : PubMed/NCBI
34	Szablewski L: Expression of glucose transporters in cancers. Biochim Biophys Acta. 1835:164–169. 2013.PubMed/NCBI
35	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
36	Swietach P, Hulikova A, Vaughan-Jones RD and Harris AL: New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene. 29:6509–6521. 2010. View Article : Google Scholar : PubMed/NCBI
37	Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, et al: Targeting tumor hypoxia: Suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 71:3364–3376. 2011. View Article : Google Scholar : PubMed/NCBI
38	Sato M, Harada-Shoji N, Toyohara T, Soga T, Itoh M, Miyashita M, Tada H, Amari M, Anzai N, Furumoto S, et al: L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism. Sci Rep. 11:5892021. View Article : Google Scholar : PubMed/NCBI
39	Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, Asara JM, Brown M and Muthuswamy SK: LLGL2 rescues nutrient stress by promoting leucine uptake in ER⁺ breast cancer. Nature. 569:275–279. 2019. View Article : Google Scholar : PubMed/NCBI