Breast Mammographic Density: Stromal Implications on Breast Cancer Detection and Therapy

Abstract

Current evidences state clear that both normal development of breast tissue as well as its malignant progression need many-sided local and systemic communications between epithelial cells and stromal components. During development, the stroma, through remarkably regulated contextual signals, affects the fate of the different mammary cells regarding their specification and differentiation. Likewise, the stroma can generate tumour environments that facilitate the neoplastic growth of the breast carcinoma. Mammographic density has been described as a risk factor in the development of breast cancer and is ascribed to modifications in the composition of breast tissue, including both stromal and glandular compartments. Thus, stroma composition can dramatically affect the progression of breast cancer but also its early detection since it is mainly responsible for the differences in mammographic density among individuals. This review highlights both the pathological and biological evidences for a pivotal role of the breast stroma in mammographic density, with particular emphasis on dense and malignant stromas, their clinical meaning and potential therapeutic implications for breast cancer patients.

Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis

“…The DCIS TME shows a high variability in composition and collagen amounts and in the topological distribution of stromal cells, including fibroblasts [18][19][20][21]. In fact, high collagen deposition and high mammographic density (HMD) are closely related to increased risk of BrCa [22]. The transcriptional profile of fibroblasts present in HMD samples indicated that they are prone to over-activate stress response, inflammation, stemness and C-Jun N-terminal kinase 1(JNK1) pathway and expression patterns similar to those of CAFs in BrCa [23].…”

Effect of the Intake of Isoflavones on Risk Factors of Breast Cancer—A Systematic Review of Randomized Controlled Intervention Studies

“…Risk factors in serum include free E 2 , insulin-like growth factor 1 (IGF-1), the ratio of IGF-1 to IGF binding protein 3 (IGFBP-3), single nucleotide polymorphisms, and breast intra-epithelial neoplasia. An increased breast density is associated with changes in the microenvironment (increased secretion of inflammatory molecules, cytokines, growth factors) that favor tumor growth [ 19 ], and with a reduced renal excretion of estrogens [ 20 ]. Estrogens stimulate the expression of genes involved in cell growth and inflammation [ 21 ].…”

Body Mass Index Is Inversely Associated with Risk of Postmenopausal Interval Breast Cancer: Results from the Women’s Health Initiative

“…Lean women have an increased risk of dense breasts, which is a strong risk factor for breast cancer [22], including interval breast cancer [23]. Biologically, mammographic density is associated with breast stroma composition [24] with dense areas especially associated with higher pro-tumor fibrillar collagen deposition [25]. Collagen can directly increase the matrix stiffness and indirectly modulate mammary fibroblast secretion of soluble factors such as transforming growth factor beta, insulin-growth factor, and epidermal growth factor to promote tumorigenesis [24], leading to tumor progression.…”

“…Biologically, mammographic density is associated with breast stroma composition [24] with dense areas especially associated with higher pro-tumor fibrillar collagen deposition [25]. Collagen can directly increase the matrix stiffness and indirectly modulate mammary fibroblast secretion of soluble factors such as transforming growth factor beta, insulin-growth factor, and epidermal growth factor to promote tumorigenesis [24], leading to tumor progression. Determining associations between obesity and interval breast cancer, as performed in this current study, could inform future efforts to understand and target the influence of BMI and associated adipose tissue on the underlying tumor biology and or masking of interval breast cancers.…”