Cholesterol de novo Biosynthesis in Paired Samples of Breast Cancer and Adjacent Histologically Normal Tissue: Association with Proliferation Index, Tumor Grade, and Recurrence-Free Survival

Cholesterol is an essential component of cell membranes whose local de novo biosynthesis may occur in response to additional cellular requirements, especially cell proliferation. In this study, we investigated: (1) the differential expression of the genes coding for the main enzymes involved in cholesterol biosynthesis (ACAT2, HMGCS1, HMGCR, FDFT1, SQLE, LSS, and NSDHL), or the proteins that control their activity (SREBF2, SCAP, and INSIG1), in patient-matched samples of breast cancer and adjacent histologically normal (HN) tissue; (2) their association with the expression of MKI67 or the histologic tumor grade (in particular, G2); (3) their association with recurrence-free survival (RFS).

Nonparametric rank-based models for longitudinal data were applied to assess the differential gene expression between the tumor and the adjacent HN tissue from the same patient or between the classes of tumor grade. Spearman’s rank correlation and Cox proportional hazard models were used to assess the correlation between the genes and their association with RFS.

Compared to the adjacent HN tissue, HMGCS1, HMGCR, SQLE, and NSDHL genes were more expressed in the tumor. Their expression progressively increased according to tumor grade and correlated positively with MKI67. ACAT2, HMGCR, and NSDHL genes were associated with a high risk of recurrence even when adjusted for age, tumor grade, or immunohistochemical Ki67.

The findings indicated that some genes involved in cholesterol biosynthesis were more expressed in cancerous tissue, correlated positively with tumor grade and MKI67 expression, and were associated with RFS, thus substantiating the relationship between de novo cholesterol biosynthesis and tumor aggressiveness.