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Review
. 2012 Apr;295(4):553-62.
doi: 10.1002/ar.22417. Epub 2012 Jan 24.

Microenvironmental Control of the Breast Cancer Cell Cycle

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Free PMC article
Review

Microenvironmental Control of the Breast Cancer Cell Cycle

Xun Guo et al. Anat Rec (Hoboken). .
Free PMC article

Abstract

The mammary gland is one of the best-studied examples of an organ whose structure and function are influenced by reciprocal signaling and communication between cells and their microenvironment. The mammary epithelial cell (MEC) microenvironment includes stromal cells and extracellular matrix (ECM). Abundant evidence shows that the ECM and growth factors co-operate to regulate cell cycle progression, and that the ECM is altered in breast tumors. In particular, mammographically dense breast tissue is a significant risk factor for developing breast carcinomas. Dense breast tissue is associated with increased stromal collagen and epithelial cell content. In this article, we overview recent studies addressing the effects of ECM composition on the breast cancer cell cycle. Although the normal breast ECM keeps the MEC cycle in check, the ECM remodeling associated with breast cancer positively regulates the MEC cycle. ECM effects on the downstream biochemical and mechanosignaling pathways in both normal and tumorigenic MECs will be reviewed.

Figures

Figure 1
Figure 1
Model of a mammary epithelial cell duct in a compliant versus stiff collagen matrix. (A) In a compliant matrix, MECs organize into polarized acini and ductal structures. (B) A collagen dense matrix promotes MEC proliferation and migration.
Figure 2
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.
Figure 3
Figure 3
Integration of environmental cues including growth factors, cell–cell contacts and ECM regulates proliferation. (A) A compliant ECM and contact with neighboring cells impose constraints on epithelial cell proliferation. (B) Increased ECM stiffness reduces the threshold amount of EGF needed to override contact inhibition and stimulates proliferation. Loss of contact inhibition coincides with disruption of cell-cell contacts, change in localization of EGFR and ZO-1, and enchanced ERK signalling (Kim and Asthagiri, 2011). MECs also respond to increased matrix stiffness in a FAK-dependent manner by developing mature focal adhesions, upregulating a FAK-Rho signalling loop and ERK activation, which stimulates contraction, migration and proliferation.

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