How integrins control breast biology

Abstract

This article explores new ideas about how the ECM-integrin axis controls normal and malignant breast biology. We discuss the role of integrins in mammary stem cells, and how cell-matrix interactions regulate ductal and alveolar development and function. We also examine the contribution of integrins to tissue disorganisation and metastasis, and how an altered stromal and ECM tumour microenvironment affects the cancer cell niche both within primary tumours and at distant sites. Finally, we mention novel strategies for integrin-directed breast cancer treatment.

Figure 1

(a) Mammary gland from 14.5-day-pregnant mouse stained in whole-mount with Carmine-Alum, showing ducts and lobules embedded within connective tissue stroma. (b) A section through a mammary gland from 14.5-day-pregnant mouse stained with H&E, showing the discrete organisation of epithelial alveoli and ducts surrounded by the stromal ECM. The whole epithelial structure is embedded within the connective tissue stroma, largely containing adipocytes in the mouse. (c) A section through an invasive mammary tumour developed in K5ΔNβcat mouse (courtesy of Aurélie Chiche). Note that the tissue architecture is completely disrupted. Bars: (a) 0.5 mm, (b,c) 0.2 mm.

Figure 2

(a) Diagram of a part mammary alveolus showing key functional integrin-dependent forces identified by genetic analyses. β1-integrins are required for luminal cells to orientate their polarity so that they can secrete milk apically into lumens, and for myoepithelial cells to complete the stretch-relax cycles needed for milk ejection. (b) Epithelial cell function depends on the integration a variety of microenvironmental signals, including those from GFs, cell–ECM and cell–cell interactions, and from biomechanical forces. (c) Cell–ECM interactions can regulate transcription and cell phenotype directly by a series of mechanical links between ECM, acto-myosin cytoskeleton, the LINC nuclear membrane complex, and nuclear cytoskeleton.

Figure 3

(a) Integrins and integrin signalling proteins are upregulated or activated at the primary breast tumour site. This leads to tissue disorganisation and loss of polarity. The stromal ECM changes, becoming stiffer. Together changes in integrin signalling promote increased proliferation, reduced apoptosis, and enhanced migration. (b) Tumour cells influence cell–ECM interactions at the secondary site by remodelling the stromal niche. This can occur in a variety of ways, including direct expression of proteins normally expressed in embryogenesis (tenascin), and indirect remodelling via stromal cell intermediates, for example in the expression of periostin.