From ductal carcinoma in situ to invasive breast cancer: the prognostic value of the extracellular microenvironment.

Abstract

Ductal carcinoma in situ (DCIS) is a noninvasive breast disease that variably progresses to invasive breast cancer (IBC). Given the unpredictability of this progression, most DCIS patients are aggressively managed similar to IBC patients. Undoubtedly, this treatment paradigm places many DCIS patients at risk of overtreatment and its significant consequences. Historically, prognostic modeling has included the assessment of clinicopathological features and genomic markers. Although these provide valuable insights into tumor biology, they remain insufficient to predict which DCIS patients will progress to IBC. Contemporary work has begun to focus on the microenvironment surrounding the ductal cells for molecular patterns that might predict progression. In this review, extracellular microenvironment alterations occurring with the malignant transformation from DCIS to IBC are detailed. Not only do changes in collagen abundance, organization, and localization mediate the transition to IBC, but also the discrete post-translational regulation of collagen fibers is understood to promote invasion. Other extracellular matrix proteins, such as matrix metalloproteases, decorin, and tenascin C, have been characterized for their role in invasive transformation and further demonstrate the prognostic value of the extracellular matrix. Importantly, these extracellular matrix proteins influence immune cells and fibroblasts toward pro-tumorigenic phenotypes. Thus, the progressive changes in the extracellular microenvironment play a key role in invasion and provide promise for prognostic development.