Tissue architecture and breast cancer: the role of extracellular matrix and steroid hormones

Abstract

The changes in tissue architecture that accompany the development of breast cancer have been the focus of investigations aimed at developing new cancer therapeutics. As we learn more about the normal mammary gland, we have begun to understand the complex signaling pathways underlying the dramatic shifts in the structure and function of breast tissue. Integrin-, growth factor-, and steroid hormone-signaling pathways all play an important part in maintaining tissue architecture; disruption of the delicate balance of signaling results in dramatic changes in the way cells interact with each other and with the extracellular matrix, leading to breast cancer. The extracellular matrix itself plays a central role in coordinating these signaling processes. In this review, we consider the interrelationships between the extracellular matrix, integrins, growth factors, and steroid hormones in mammary gland development and function.

Figure 1

Integration of structure and function by the ECM. The ECM, an essential component of the mammary gland, is intimately involved in processes that determine tissue architecture (reviewed in Bissell et al. 1999).

Figure 2

The structure of the mammary gland is dependent on the developmental stage. The adult female mammary gland experiences recurrent cycles of regulated growth, differentiation, and apoptosis, and estrogen and progesterone play a central role in this process. The cycles that occur in the mammary gland can be divided into several stages: puberty, pregnancy, lactation, and involution. Each stage can be further described by the structure of the gland, called lobules or Lobs (reviewed in Russo & Russo 1998).

Figure 3

Models to study the role of ECM and steroid hormones. Culture and animal models provide complementary systems for the study of breast structure and function. Cells from the HMT-3522 human breast cancer series exhibit similar phenotypes in 2D cultures on plastic, but exhibit very different phenotypes in 3D cultures in rBM. S1 cells form phenotypically normal structures reminiscent of terminal ductal lobular units, with regular boundaries, and T4-2 cells form disorganized clusters with irregular boundaries and dissemination into the EHS (reviewed in Bissell et al. 1999). Although mouse mammary tissue varies somewhat with respect to the overall mammary gland organization, it is now clear that there are many similarities. As such, the mouse has been a valuable model for studying the effects of ER and PR function.

Figure 4

Tissue architecture integrates, and in turn depends on, the integration of signals from ECM and its receptors, growth factors and their receptors, and steroid hormones and their receptors.