Figure 2.

Model for cell cycle regulation of mammary epithelial cells by increased ECM density/stiffness. (A) As cells encounter increased resistance to contractility from stiff matrices such as a collagen dense stroma (blue lines), they respond by integrin clustering (red), which leads to phosphorylation and activation of focal adhesion kinase (FAK). This activates a FAK-ERK-Rho signaling loop that induces transcription factors such as c-myc, which stimulate transcription of G₁ cyclins (cyclins D and E). Cyclin D (cyc D) and cyclin E (cyc E) activate cdks and facilitate progression through G₁ into S phase. Phosphorylation of myosin light chain downstream of Rho-GTP increases cellular contractility, generating tension that is also required for proliferation. (B) In a pliable stroma, integrin clustering is not induced thus downstream signalling pathways are not activated.