SLC22A5/OCTN2 expression in breast cancer is induced by estrogen via a novel intronic estrogen-response element (ERE)
Open accessAbstract
Estrogen signaling is a critical pathway that plays a key role in the pathogenesis of breast cancer. In a previous transcriptional profiling study, we identified a novel panel of estrogen-induced genes in breast cancer. One of these genes is solute carrier family 22 member 5 (SLC22A5), which encodes a polyspecific organic cation transporter (also called OCTN2). In this study, we found that estrogen stimulates SLC22A5 expression robustly in an estrogen receptor (ER)-dependent manner and that SLC22A5 expression is associated with ER status in breast cancer cell lines and tissue specimens. Although the SLC22A5 proximal promoter is not responsive to estrogen, a downstream intronic enhancer confers estrogen inducibility. This intronic enhancer contains a newly identified estrogen-responsive element (ERE) (GGTCA-CTG-TGACT) and other transcription factor binding sites, such as a half ERE and a nuclear receptor related 1 (NR4A2/Nurr1) site. Estrogen induction of the luciferase reporter was dependent upon both the ERE and the NR4A2 site within the intronic enhancer. Small interfering RNA against either ER or Nurr1 inhibited estrogen induction of SLC22A5 expression, and chromatin immunoprecipitation assays confirmed the recruitment of both ER and Nurr1 to this enhancer. In functional assays, knockdown of SLC22A5 inhibited L: -carnitine intake, resulted in lipid droplet accumulation, and suppressed the proliferation of breast cancer cells. These results demonstrate that SLC22A5 is an estrogen-dependent gene regulated via a newly identified intronic ERE. Since SLC22A5 is a critical regulator of carnitine homeostasis, lipid metabolism, and cell proliferation, SLC22A5 may serve as a potential therapeutic target for breast cancer in the future.
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SLC22A5 is a carnitine transporter involved in neurotransmitter synthesis.
“SLC22A5 is a carnitine transporter involved in neurotransmitter synthesis, and expression of SLC22A5 is regulated by estrogen receptors. 62”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [62]
The Results section identifies SLC22A5 as a carnitine transporter, and the Abstract reports that estrogen stimulates its expression in an estrogen receptor-dependent manner. The paper discusses carnitine transport and lipid metabolism, but does not support the attributed involvement in neurotransmitter synthesis; a search for that phrase found no relevant passage. Page numbers were not provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSLC22A5 is associated with estrogen-related signaling pathways.
“Both PLCD3 and SLC22A5 are associated with estrogen‐related signaling pathways (Figure S5), with PLCD3 being a phospholipase C (PLC) isozyme activated by G protein‐coupled estrogen receptor (GPER) 60 , 61 and SLC22A5 being a carnitine transport protein transcriptionally regulated by estrogen receptors. 62”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [62]
SLC22A5 is a carnitine transport protein transcriptionally regulated by estrogen receptors.
“Both PLCD3 and SLC22A5 are associated with estrogen‐related signaling pathways (Figure S5), with PLCD3 being a phospholipase C (PLC) isozyme activated by G protein‐coupled estrogen receptor (GPER) 60 , 61 and SLC22A5 being a carnitine transport protein transcriptionally regulated by estrogen receptors. 62”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [62]
Expression of SLC22A5 is regulated by estrogen receptors.
“SLC22A5 is a carnitine transporter involved in neurotransmitter synthesis, and expression of SLC22A5 is regulated by estrogen receptors. 62”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [62]
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- Authors
- Wang, C., Uray, I. P., Mazumdar, A., Mayer, J. A., & Brown, P. H.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Brown, Powel H.
- Venue
- Breast Cancer Research and Treatment
- Published
- 2012-01-03
- Volume
- 134
- Issue
- 1
- Pages
- 101-115
- ISSN
- 0167-6806 (ISSN-L)
- 1573-7217
- PMC
- PMC3416040
- OpenAlex
- W2013709205
- Cited by
- 59
- References
- 62
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 3
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Breast Cancer Research and Treatment (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- Funders
- National Cancer Institute (R01CA123246)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SLC22A5, OCTN2, breast cancer, estrogen signaling, estrogen receptor, intronic enhancer, estrogen response element, Nurr1, organic cation transporters, carnitine homeostasis, lipid droplet accumulation, cell proliferation, transcriptional regulation
- MeSH terms
- Solute Carrier Family 22 Member 5, Base Sequence, Binding Sites, Breast Neoplasms, Carnitine, Estrogens, Female, Humans, Introns, Luciferases, Protein Binding, Receptors, Estrogen, Gene Expression, Gene Expression Regulation, Neoplastic, Genes, Reporter, Response Elements, Organic Cation Transport Proteins, Cell Line, Tumor, Cell Proliferation, Lipid Metabolism, Nuclear Receptor Subfamily 4, Group A, Member 2
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