An "elite hacker": breast tumors exploit the normal microenvironment program to instruct their progression and biological diversity

Abstract

The year 2011 marked the 40 year anniversary of Richard Nixon signing the National Cancer Act, thus declaring the beginning of the "War on Cancer" in the United States. Whereas we have made tremendous progress toward understanding the genetics of tumors in the past four decades, and in developing enabling technology to dissect the molecular underpinnings of cancer at unprecedented resolution, it is only recently that the important role of the stromal microenvironment has been studied in detail. Cancer is a tissue-specific disease, and it is becoming clear that much of what we know about breast cancer progression parallels the biology of the normal breast differentiation, of which there is still much to learn. In particular, the normal breast and breast tumors share molecular, cellular, systemic and microenvironmental influences necessary for their progression. It is therefore enticing to consider a tumor to be a "rogue hacker"--one who exploits the weaknesses of a normal program for personal benefit. Understanding normal mammary gland biology and its "security vulnerabilities" may thus leave us better equipped to target breast cancer. In this review, we will provide a brief overview of the heterotypic cellular and molecular interactions within the microenvironment of the developing mammary gland that are necessary for functional differentiation, provide evidence suggesting that similar biology--albeit imbalanced and exaggerated--is observed in breast cancer progression particularly during the transition from carcinoma in situ to invasive disease. Lastly we will present evidence suggesting that the multigene signatures currently used to model cancer heterogeneity and clinical outcome largely reflect signaling from a heterogeneous microenvironment-a recurring theme that could potentially be exploited therapeutically.

Figure 1. Dynamic microenvironments regulate both normal mammary gland development and malignant progression. Branching morphogenesis during normal mammary gland development requires an extensive dialog between epithelial and stromal cells and their underlying extracellular matrix (ECM). These events resurface or are amplified during malignancy, and often are required for cancer progression. As such, the microenvironment represents a “security vulnerability” through which tumors can “hack” the normal developmental “program” to manifest themselves.