Background <p>Breast cancer is the second leading cause of cancer-related death among women in the United States. High mammographic density, one of the most notable risk factors, is associated with a four to sixfold increased likelihood of developing breast cancer. Tissue compactness is a related but distinct, newly developed tool to assess density in a specific location. However, the transcriptomic differences between more and less compact tissue are not well understood.</p> Methods <p>We performed RNA sequencing on paired more and less-compact breast tissue from three individuals to identify genes that correlate with compactness.</p> Results <p>We identified 8 genes that were differentially expressed between more and less compact tissue. Less-compact tissue had an upregulation of genes associated with an immunosuppressive microenvironment, consistent with higher estimated fractions of t-regulatory cells. Pathway analysis revealed that more compact tissue is significantly enriched for cholesterol homeostasis genes; cholesterol biosynthesis has been demonstrated to promote breast cancer and its metastasis.</p> Conclusions <p>This study provides novel insights into the transcriptomic differences between more and less compact breast tissue and represents an important step towards understanding the molecular distinctions between tissue compactness and breast cancer risk.</p>