Integrated extracellular matrix signaling in mammary gland development and breast cancer progression

Abstract

Extracellular matrix (ECM), a major component of the cellular microenvironment, plays critical roles in normal tissue morphogenesis and disease progression. Binding of ECM to membrane receptor proteins, such as integrin, discoidin domain receptors, and dystroglycan, elicits biochemical and biomechanical signals that control cellular architecture and gene expression. These ECM signals cooperate with growth factors and hormones to regulate cell migration, differentiation, and transformation. ECM signaling is tightly regulated during normal mammary gland development. Deposition and alignment of fibrillar collagens direct migration and invasion of mammary epithelial cells during branching morphogenesis. Basement membrane proteins are required for polarized acinar morphogenesis and milk protein expression. Deregulation of ECM proteins in the long run is sufficient to promote breast cancer development and progression. Recent studies demonstrate that the integrated biophysical and biochemical signals from ECM and soluble factors are crucial for normal mammary gland development as well as breast cancer progression.

Figures

Figure 1

Mammary gland epithelial cells form polarized acinar structures when cultured in 3D matrigel. Treatment with prolactin can activate JAK2-STAT5 pathway. Without laminin-111, STAT5 only shows a transient phosphorylation, which is not suffcient for chromatin remodeling and milk gene expression. After laminin-111 binds integrins and dystroglycan, PI3K re-localize to the basal surface. Rac1 is a downsteam target of PI3K and required for sustained activation of STAT5. Prolactin, together with laminin-111, induces histone acetylation, binding of the SWI/SNF and transcription factors to the promoter and initiates transcription of casein.

Figure 2

Matrix stiffness induces integrin clustering and activation of PI3K and Rho in breast cancer cells. Integrin clustering enhances growth factor-dependent ERK activation and increases ROCK expression lever. Increased cell tension reduces turnover of lamin A. Accumulation of lamin A drives translocation of the retinoic acid receptor (RARG) into nucleus and RARG lead the transcription of Lamin-A. Rho and Lamin-A can translocate YAP/TAZ. YAP regulates the expression of several cytoskeletal regulators, including MLC.