The Role of the Microenvironment in Mammary Gland Development and Cancer

Abstract

The mammary gland is composed of a diverse array of cell types that form intricate interaction networks essential for its normal development and physiologic function. Abnormalities in these interactions play an important role throughout different stages of tumorigenesis. Branching ducts and alveoli are lined by an inner layer of secretory luminal epithelial cells that produce milk during lactation and are surrounded by contractile myoepithelial cells and basement membrane. The surrounding stroma comprised of extracellular matrix and various cell types including fibroblasts, endothelial cells, and infiltrating leukocytes not only provides a scaffold for the organ, but also regulates mammary epithelial cell function via paracrine, physical, and hormonal interactions. With rare exceptions breast tumors initiate in the epithelial compartment and in their initial phases are confined to the ducts but this barrier brakes down with invasive progression because of a combination of signals emitted by tumor epithelial and various stromal cells. In this article, we overview the importance of cellular interactions and microenvironmental signals in mammary gland development and cancer.

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

“…Emerging concepts in cancer metastasis emphasize the role of the tumor stroma in regulating the metastatic cascade and suggest that cancer cells are highly responsive to the contextual signals of nearby stromal cells (2). In this context, the induction of EMT and CSC phenotypes in the cancer cells by stromal MSCs is consistent with the transient nature of such contextual signals, because both EMT and CSC programs may need to be reversed to allow for the completion of the metastatic cascade (22).…”

“…This mesenchymal microenvironment is integral for tumor initiation and growth, because it regulates the survival and proliferation of neoplastic cells and the overall dynamics of tumor development (2). Therefore, defining the nature of the signals exchanged between the stromal niche and the cancer cells should provide insights into how breast cancers develop and progress and reveal therapeutic modalities based on intercepting the tumorstroma cross-talk.…”

Stromal Signatures of Breast Carcinogenesis in Fibroadenoma—A Pilot Study

“…The 'cross-talk' between these two elements is an ill-understood yet key line of communication that begins in normal breast during embryological development when the epithelial and mesenchymal cells communicate to ensure proper development and function [1]. The proliferation, survival, polarity, differentiation, and invasive capacity of mammary epithelia are modified by various stromal cells within the microenvironment [27]. Interestingly, these processes are important not only in the development of the normal breast but can reoccur after maturation, at which point they are considered mechanisms for tumourigenesis.…”

Paracrine signaling in stem cell renewal and in neoplastic tumor growth

“…Deregulation of epithelial-stromal interactions is often associated with diseases that affect epithelial cell growth, such as in tumorigenesis [1]. Despite progress in understanding the activities and roles of epithelial-stromal interactions in various tissues and diseases, little has been known about the signaling pathways that directly regulate epithelial-stromal crosstalk.…”

“…Epithelial and stromal interactions play critical roles in embryonic development, adult tissue homeostasis [1], and injury-induced regeneration [2]. Deregulation of epithelial-stromal interactions is often associated with diseases that affect epithelial cell growth, such as in tumorigenesis [1].…”