Ternary Complex Components Responsible for Rapid LDL Internalization as Biomarkers for Breast Cancer Associated with Proliferation and Early Recurrence.

abstractThe ternary complex of progesterone receptor membrane component 1 (PGRMC1)–sigma-2 receptor/transmembrane protein 97 (σ2R/TMEM97)–low-density lipoprotein receptor (LDLR) has recently been discovered and plays a role in cholesterol transport. This study investigated whether individual components of that complex are prognostic breast cancer biomarkers and have defined expression in established molecular subtypes. A total of 4,463 invasive breast cancers were analyzed as a function of molecular and phenotypic markers, estimates of cellular proliferation, and recurrence-free survival. A gene expression signature–based assay was utilized to estimate cellular proliferation. Cox proportional hazards regression estimated relapse-free survival and multivariate Cox analysis adjusted for the association of proliferation with early relapse. PGRMC1–σ2R/TMEM97–LDLR expression was stratified by immunohistochemical (IHC) and molecular subtype, tumor grade, and size. TMEM97 exhibited the strongest correlation with proliferation, highest in estrogen receptor (ER)–positive disease (r = 0.59, P = 8.1−114). TMEM97 and PGRMC1 were associated with a risk of early recurrence, dependent upon their association with proliferation. The risk of early recurrence was highest with TMEM97 and only seen in ER+/HER2− disease [HR = 1.5; 95% confidence interval (CI) = 1.35–1.67; P = 5.4−14] and ER+ malignancies (HR = 1.49; 95% CI = 1.31–1.68; P = 3.1−10). There was no increased risk of recurrence with TMEM97 expression in ER−/HER2− (HR = 1.05; 95% CI = 0.88–1.25; P = 0.63) or ER− disease (HR = 1.02; 95% CI = 0.89–1.17; P = 0.75). Components of a ternary complex associated with rapid internalization of low-density lipoprotein are biomarkers associated with cellular proliferation and early recurrence, which should help guide studies exploring them in the context of additional markers of aggressive disease. Elucidating the role of PGRMC1, TMEM97, and LDLR in breast cancer will facilitate a mechanistic understanding of how proliferation interplays with cholesterol metabolism in malignant transformation or propagation. SIGNIFICANCE: This first large-scale analysis of the putative ternary complex responsible for rapid low-density lipoprotein internalization in breast cancer reveals a link between component expression and recurrence, with prognostic implications for identifying patients needing supplemental posttreatment surveillance and/or additional therapeutic approaches.