Breast cancer is one of the most common types of cancer affecting women in the world today. To better understand breast cancer initiation and progression modeling biological tissue under physiological conditions is essential. Indeed, breast cancer involves complex interactions between mammary epithelial cells and the stroma, both extracellular matrix (ECM) and cells including adipocytes (fat tissue) and fibroblasts (connective tissue). Therefore, the engineering of in vitro three-dimensional (3D) systems of breast tissues allows a deeper understanding of the complex cell-cell and cell-ECM interactions involved during breast tissue development and cancer initiation and progression. Furthermore, such 3D systems may provide a viable alternative to investigate new drug or drug regimen and to model and monitor concurrent cellular processes during tumor growth and invasion. The development of suitable 3D in vitro models relies on the ability to mimic the microenvironment, the structure, and the functions of the breast tissue. Different approaches to develop a novel 3D breast model have been investigated. Most models use gel scaffolds, including Matrigel® and collagen to generate breast tissue-like structures. However, the physicochemical, mechanical, and geometrical properties of these scaffolds only partially meet the mechanical, physical, and chemical parameters of the breast tissue matrix. In the present studies, we investigated the overall hypothesis that electrospun SF-derived scaffolds promote mammary cell growth and the formation of mammary-like structures depending on the composition and/or coating of the scaffolds with ECM proteins. Through an extensive literature search (1) the importance of 3D modeling of tissues and organs in vivo, (2) 3D modeling of the mammary tissue and currently available models, (3) the properties and applications of SF in tissue modeling and regeneration were reviewed (Chapter 1). Our studies provide evidence of the effects of various concentrations (Chapter 2) of SF along with different electrospinning techniques (Chapter 3) on the structure of electrospun scaffolds and whether those scaffolds provide suitable microenvironments for mammary epithelial cells as determined by MCF10A cell attachment, viability, and structure formation. Further, we investigated the effects of the key ECM proteins collagen I (Chapter 4) and laminin (Chapter 5) used to blend or coat, respectively, SF scaffolds on the attachment, viability and structure formation of mammary epithelial cells. Our studies first highlight the mechanical and physical properties of the different SF-derived scaffolds through various SF concentrations and electrospinning techniques. Second, the biocompatibility of these SF electrospun scaffolds was defined based on MCF10A cell survival and adhesion. Third, our data indicate that scaffolds derived from blended and/or coated SF with collagen I also promoted human mammary cell survival and adhesion. Lastly, our observations suggest that on laminin-coated SF scaffolds MCF10A mammary cells, in the presence of lactogenic hormones, differentiated forming acinus-like structures. Overall, these studies provide evidence that SF electrospun scaffolds closely mimic the structure of the ECM fibers and allow many advantages such as; physical and chemical modification of the microenvironment by varying electrospinning parameters and addition of various proteins, hormones, and growth factors, respectively. Further, coating these SF scaffolds with essential ECM proteins, in particular laminin, promote cell-ECM interactions necessary for cell differentiation and formation of growth-arrested structures, through providing cell integrin binding sites and appropriate chemical cues.