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Mechanisms by Which the Extracellular Matrix and Integrin Signaling Act to Regulate the Switch Between Tumor Suppression and Tumor Promotion

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Abstract

Cell adhesion to the extracellular matrix (ECM) is necessary for development of the mammary gland, and to maintain the normal architecture and function of the gland. Cells adhere to the ECM via the integrin family of trans-membrane receptors, which signal to control mammary-specific gene expression and regulate cell proliferation and survival. During tumor formation, the ECM is extensively remodeled and signaling through integrins is altered such that cells become proliferative and invasive. A key regulator of whether integrin-mediated adhesion will promote tumor suppression or tumor formation is the stiffness of the stromal ECM. The normal mammary gland is typically surrounded by a loose collagenous stroma. An increase in the deposition of collagen and other stromal components is associated with mammographic density, which is one of the greatest risk factors for developing breast carcinoma. Several groups have demonstrated that increased stromal ECM density results in a matrix that is stiffer. Cells sense the stiffness of their surrounding ECM by Rho-mediated contraction of the actin-myosin cytoskeleton. If the surrounding ECM is stiffer than the cell’s ability to contract it, then the tensile forces that result are able to drive the clustering of integrins and assemble adhesion signaling complexes. The result is subsequent activation of signaling pathways including FAK, ERK, and PI3K that drive cell proliferation and survival. In contrast, focal complexes are not formed in a compliant matrix, and activation of FAK and pERK is diminished, resulting in control of proliferation. Signaling from FAK moreover regulates p53 and miR-200 members, which control apoptosis and epithelial phenotype, such that a compliant matrix is predicted to promote normal mammary gland architecture and suppress tumor formation.

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Abbreviations

ECM:

extracellular matrix

FAK:

focal adhesion kinase

ERK:

extracellular regulated kinase

PI3K:

phosphoinositol-3-kinase

MEC:

mammary epithelial cell

GAP:

GTPase-activating protein

GEF:

guanine nucleotide exchange factor

BL:

basal lamina

TEB:

terminal end bud

DCIS:

ductal carcinoma in situ

MLC:

myosin light chain

LN:

laminin

FN:

fibronectin

EGFR:

Epidermal growth factor receptor

PABC:

pregnancy associated breast cancer

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  1. Department of Cell and Regenerative Biology, Laboratory for Cellular and Molecular Biology, & Laboratory for Optical and Computational Instrumentation, University of Wisconsin, 227D Bock Laboratories, 1525 Linden Drive, Madison, WI, 53706, USA

    Patricia J. Keely

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Keely, P.J. Mechanisms by Which the Extracellular Matrix and Integrin Signaling Act to Regulate the Switch Between Tumor Suppression and Tumor Promotion. J Mammary Gland Biol Neoplasia 16, 205–219 (2011). https://doi.org/10.1007/s10911-011-9226-0

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