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Preventive actions for chronic diseases hold the promise of improving lives and reducing healthcare costs. For several diseases, including breast cancer, multiple risk and protective factors have been identified by epidemiologists. The impact of most of these factors has yet to be fully understood at the organism, tissue, cellular and molecular levels. Importantly, combinations of external and internal risk and protective factors involve cooperativity thus, synergizing or antagonizing disease onset. Models are needed to mechanistically decipher cancer risks under defined cellular and microenvironmental conditions. Here, we briefly review breast cancer risk models based on 3D cell culture and propose to improve risk modeling with lab-on-a-chip approaches. We suggest epithelial tissue polarity, DNA repair and epigenetic profiles as endpoints in risk assessment models and discuss the development of 'risks-on-chips' integrating biosensors of these endpoints and of general tissue homeostasis. Risks-on-chips will help identify biomarkers of risk, serve as screening platforms for cancer preventive agents, and provide a better understanding of risk mechanisms, hence resulting in novel developments in disease prevention.

Improved detection and therapy of breast neoplasia might benefit from nanodevices traveling inside mammary ducts. However, the decreasing size of branched mammary ducts prevents access to remote areas of the ductal system using a pressure-driven fluid-based approach. Magnetic field guidance of superparamagnetic submicron particles (SMPs) in a stationary fluid might provide a possible alternative but it is critical to first reproduce the breast ductal system to assess the use of such devices for future therapeutic & diagnostic (“theranostic”) purposes. Here we describe the engineering of a portion of a breast ductal system using polydimethylsiloxane (PDMS) microfluidic channels with a total volume of 0.09 μl. A magnet was used to move superparamagnetic/fluorescent SMPs through a static fluid inside the microchannels. Non-neoplastic mammary epithelial S1 cells developed basoapical polarity as a flat monolayer on the PDMS surface when cultured in the presence of laminin 111, and incubation with SMPs did not result in detectable toxicity. Cells could not withstand the fluid pressure if microinjected directly in completed channels. Whereas, they readily covered laminin 111-coated PDMS surfaces when cultured in U-shaped “hemichannels” before completing the channels. This breast-on-chip model represents a critical step towards the mimicry of the tree-like ductal system of the breast for further testing and targeting of SMPs.