Uncontrolled proliferation of tumor cells leads to the buildup of solid stresses within growing tumors. In vivo, compressive stresses in the range of 3–13 kPa have been reported in malignant breast tumors, and such stresses can collapse blood vessels, promote hypoxia, and enhance metastatic potential. Because breast tumors expand slowly over months to years before detection, cancer cells have ample time to adapt mechanically and remodel the surrounding extracellular matrix (ECM). Although cells are known to sense and respond to mechanical cues, most mechanobiological studies have focused on tensile forces or fluid shear. By comparison, far less is understood about how solid compressive stress influences tumor mechanics and molecular signaling.This dissertation develops in vitro experimental platforms that recreate physiologically relevant solid stresses, with a particular emphasis on compression. Two in vitro systems, a modified Transwell platform and a microfluidic compression device, were used to apply uniform mechanical loading to 3D spheroids. These models enabled quantitative characterization of spheroid mechanics, revealing that mechanical compression differentially regulates breast spheroids response. Viscoelastic properties varied markedly between malignant and non-malignant spheroids, and a modified power-law framework was established to describe their relaxation dynamics. Malignant spheroids displayed slower relaxation, more fluidic and plastic behavior compared to the more elastic, rapidly recovering non-malignant spheroids. These findings highlight viscoelasticity as a key mechanical biomarker that extends beyond traditional elasticity measurements. To determine how prolonged mechanical loading alters cellular pathways, 18 hours of static compression were applied to MCF7 spheroids, followed by transcriptomic and imaging analyses. These studies identified a pronounced suppression of the interferon/STAT1 signaling axis, including reduced nuclear localization and phosphorylation of STAT1. This downregulation occurred in the absence of biochemical stimuli, indicating a direct link between compression and tumor-intrinsic cytokine signaling. The discovery that solid compressive stress modulates STAT1/IFN signaling highlights a previously unrecognized molecular consequence of mechanical loading. In parallel, the viscoelastic analyses introduce a promising direction for combining relaxation dynamics with a modified power-law framework to probe mechanical differences between spheroids, laying the groundwork for future studies aimed at establishing viscoelasticity as a robust mechanical metric. Together, these findings advance understanding of how changes and perturbations in the physical microenvironment contribute to breast cancer mechanics and progression.