Glutamate Transport Proteins and Metabolic Enzymes are Poor Prognostic Factors in Invasive Lobular Carcinoma.

Autor:	Young TA; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Bahnassy S; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Abalum TC; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.; Towson University, Towson, MD 21252., Pope EA; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.; Wake Forest University, Winston-Salem, NC 27109., Rivera AT; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Fernandez AI; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.; Department of Pathology, Yale School of Medicine, New Haven, CT 06520., Olukoya AO; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Mobin D; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Ranjit S; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057., Libbey NE; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Persaud S; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Rozeboom AM; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Chaldekas K; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057., Harris BT; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.; Departments of Neurology and Pathology, Georgetown University Medical Center, Washington, DC 20057., Madak-Erdogan Z; Department of Food Science and Human Nutrition, Cancer Center at Illinois, Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801., Sottnik JL; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045., Sikora MJ; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045., Riggins RB; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 29. Date of Electronic Publication: 2024 Sep 29.
DOI:	10.1101/2024.09.29.615681
Abstrakt:	Invasive Lobular Carcinoma (ILC) is a subtype of breast cancer characterized by distinct biological features, and limited glucose uptake coupled with increased reliance on amino acid and lipid metabolism. Our prior studies highlight the importance of glutamate as a key regulator of ILC tumor growth and therapeutic response. Here we examine the expression of four key proteins involved in glutamate transport and metabolism - SLC3A2, SLC7A11, GPX4, and GLUD1/2 - in a racially diverse cohort of 72 estrogen receptor-positive (ER+) ILC and 50 ER+ invasive ductal carcinoma, no special type (IDC/NST) patients with primary disease. All four proteins are associated with increased tumor size in ILC, but not IDC/NST, with SLC3A2 also specifically linked to shorter overall survival and the presence of comorbidities in ILC. Notably, GLUD1/2 expression is associated with ER expression in ILC, and is most strongly associated with increased tumor size and stage in Black women with ILC from our cohort and TCGA. We further explore the effects of GLUD1 inhibition in endocrine therapy-resistant ILC cells using the small-molecule inhibitor R162, which reduces ER protein levels, increases reactive oxygen species, and inhibits oxidative phosphorylation. These findings highlight a potentially important role for glutamate metabolism in ILC, particularly for Black women, and position several of these glutamate-handling proteins as potential targets for therapeutic intervention in ILC. Competing Interests: Conflict of interest: Authors declare no conflict of interest.
Databáze:	MEDLINE
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