Proteoglycans: Potential Agents in Mammographic Density and the Associated Breast Cancer Risk

Abstract

Although increased mammographic density (MD) has been well established as a marker for increased breast cancer (BC) risk, its pathobiology is far from understood. Altered proteoglycan (PG) composition may underpin the physical properties of MD, and may contribute to the associated increase in BC risk. Numerous studies have investigated PGs, which are a major stromal matrix component, in relation to MD and BC and reported results that are sometimes discordant. Our review summarises these results and highlights discrepancies between PG associations with BC and MD, thus serving as a guide for identifying PGs that warrant further research towards developing chemo-preventive or therapeutic agents targeting preinvasive or invasive breast lesions, respectively.

Mammographically dense human breast tissue stimulates MCF10DCIS.com progression to invasive lesions and metastasis

“…The breast stroma is a rich source of numerous cell types, including fibroblasts, adipocytes and extracellular matrix (ECM) proteins [36–38]. ECM comprises not only collagen but also fibronectin, proteoglycans and matrix metalloproteinase (MMP) inhibitors, which have also been shown to enhance collagen stiffness and regulate growth factors and susceptibility to BC [3, 39–43]. Although BC is of epithelial cell origin and HMD is associated with increased benign epithelial lesions [44, 45], an increasing body of data supports the hypothesis that perturbations in stromal architecture are key to establishing a pro-neoplastic environment that enhances cancer growth [46, 47].…”

Heparanase promotes Syndecan-1 expression to mediate fibrillar collagen and mammographic density in human breast tissue culturedex vivo

“…An underappreciated fact is that HMD-associated BC risk is more impactful than other known risk factors, including the BRCA1/2 BC predisposition genes, when considered on a population-wide basis (Hopper 2015). In addition to increased BC risk, evidence is also emerging that HMD is associated with increased BC recurrence (Hwang, Miglioretti et al 2007, Cil, Fishell et al 2009, Shawky, Ricciardelli et al 2015, Huang, Chen et al 2016, Shawky, Huo et al 2019) and treatment resistance (Elsamany, Alzahrani et al 2015). Thus, interventions that reduce MD may offer new avenues for the prevention, diagnosis and treatment of BC.…”

“…A standout molecular feature of HMD is the preponderance of extracellular matrix (ECM), largely comprised of collagen fibres and proteoglycans (PGs), which are carbohydrate-coated proteins (Huo, Chew et al 2014, Shawky, Ricciardelli et al 2015. Abnormalities in ECM have been implicated in many pathologies, including cancer (Lu, Weaver et al 2012).…”

“…To date, the specific components of HMD ECM that promote BC are unknown. One candidate of interest, SDC1, has been positively associated with both HMD and BC (Shawky, Ricciardelli et al 2015). HMD is approximately 60 % genetically inherited (Boyd, Dite et al 2002), and GWAS studies have identified single nucleotide polymorphisms (SNPs) in several PGs and in PGmodifying enzymes that correlate with increased BC risk (Shawky, Ricciardelli et al 2015).…”

“…HSPGs are widely involved in biological activities, including cell signalling, cell adhesion, ECM assembly, and growth factor storage (reviewed in (Nagarajan, Malvi et al 2018)). HSPGs display primarily heparan sulfate-containing glycosaminoglycan (GAG) side chains that bind growth factors, which are in turn released by the action of HPSE (Shawky, Ricciardelli et al 2015). This enzyme trims HS GAG chains from HSPGs (including SDC1), allowing the PG core proteins to be cleaved by enzymes such as MMP-9.…”