Glutamate-Handling Proteins Associate with Adverse Clinicopathologic Features and Comorbidities in Invasive Lobular Carcinoma

Abstract

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 associate with increased tumor size in ILC, with three showing stronger associations in Black women, but not in IDC/NST. Among these three proteins in ILC, GLUD1/2 uniquely associates with ER expression in all women, while GLUD1/2 and SLC3A2 are enriched in hypertensive women. GLUD1/2 and GPX4 are upregulated in endocrine therapy-resistant ILC cell lines, and pharmacological inhibition of GLUD1 reduces ER protein levels and cell viability. Together, these findings support a potentially important role for glutamate metabolism in ILC and suggest GLUD1 and other glutamate-handling proteins as candidate targets for therapeutic intervention in ILC.