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Updated: Sep 27, 2025
Changes in Mammary Gland Morphology and Breast Cancer Risk in Rats
Published on: October 16, 2010
Gene Expression Changes by Diallyl Trisulfide Administration in Chemically-induced Mammary Tumors in Rats
Eun-Ryeong Hahm1, Shivendra V Singh1,2
1Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Abstract:
Diallyl trisulfide (DATS) was shown to be a potent inhibitor of luminal-type MCF-7 xenograft growth in vivo. The present study was conducted to determine the preventive effect of DATS administration using an N-methyl-N-nitrosourea (MNU)-induced rat mammary tumor model, which shares molecular resemblance to luminal-type human breast cancers. The DATS administration (50 mg/kg body weight, 5 times/week) was safe, but did not reduce mammary tumor latency, incidence, burden or multiplicity. Therefore, we conducted RNA-seq analysis using mammary tumors from control and DATS-treated rats (n = 3 for each group) to gain insights into lack of mammary tumor prevention by this phytochemical. The gene ontology and the Kyoto encyclopedia of genes and genomes pathway analyses of the RNA-seq data revealed upregulation of genes associated with ribosomes, translation, peptide biosynthetic/metabolic process, and oxidative phosphorylation but downregulation of genes associated with mitogen-activated protein kinases. A total of 33 genes associated with ribosomes were significantly upregulated by DATS treatment, including RPL11 and RPS14. Western blotting confirmed upregulation of RPL11 and neurofascin protein expression in mammary tumors from DATS-treated rats when compared to controls. A statistically significant increase in protein level of c-Jun N-terminal kinase 2 was also observed in tumors from DATS-treated rats when compared to controls. On the other hand, expression of complex I subunits NDUFV1 or NDUFS1 was not affected by DATS treatment. These results offer potential explanations for ineffectiveness of DATS in the chemically-induced rat mammary tumor model. Inhibitors of the proteins upregulated by DATS may be needed to improve chemopreventive efficacy of this phytochemical.
Insights
Diallyl trisulfide (DATS) did not prevent N-methyl-N-nitrosourea (MNU)-induced rat mammary tumors. RNA-seq revealed DATS upregulated ribosome and translation genes, potentially explaining its ineffectiveness in this breast cancer model.
Area of Science:
- Oncology
- Chemoprevention Research
- Molecular Biology
Background:
- Diallyl trisulfide (DATS) demonstrated potent inhibition of MCF-7 xenograft growth.
- N-methyl-N-nitrosourea (MNU)-induced rat mammary tumors mimic human luminal-type breast cancers.
- Investigating DATS efficacy in a relevant preclinical model is crucial for understanding its chemopreventive potential.
Purpose of the Study:
- To evaluate the preventive effect of DATS in an MNU-induced rat mammary tumor model.
- To elucidate the molecular mechanisms underlying DATS's efficacy or lack thereof using RNA-sequencing.
Main Methods:
- Administration of DATS (50 mg/kg, 5 times/week) to rats with MNU-induced mammary tumors.
- Assessment of tumor latency, incidence, burden, and multiplicity.
- RNA-sequencing (RNA-seq) analysis of mammary tumors from control and DATS-treated groups (n=3 each).
- Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.
- Western blotting to confirm protein expression changes.
Main Results:
- DATS administration was safe but did not reduce mammary tumor latency, incidence, burden, or multiplicity.
- RNA-seq revealed significant upregulation of genes involved in ribosomes, translation, peptide biosynthesis, and oxidative phosphorylation.
- Downregulation of mitogen-activated protein kinase (MAPK) pathway genes was observed.
- Specific upregulation of ribosomal protein genes (e.g., RPL11, RPS14) and increased RPL11 and neurofascin protein levels were confirmed.
- Increased c-Jun N-terminal kinase 2 protein levels were noted, while Complex I subunits remained unaffected.
Conclusions:
- DATS did not demonstrate preventive effects in the MNU-induced rat mammary tumor model.
- Upregulation of ribosomal and translational pathways may counteract potential anti-cancer effects of DATS.
- Targeting proteins upregulated by DATS, such as those in the ribosome or MAPK pathways, might be necessary to enhance its chemopreventive efficacy.
