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We study the dynamics of tumor cell progression as growth factors and ionizing radiation (IR) combine to modify cellular microenvironments. Breast tumor growth depends on the behavior of cancer cells in their microenvironment, and both components are affected by IR fractionation parameters. TGF-β1 promotes differentiation of fibroblasts to myofibroblasts, which stiffens the extracellular matrix (ECM) and promotes malignant cell phenotypes. IR generates reactive oxygen species (ROS) that damages and inactivates cells thus controlling proliferation. The effects of TGF-β1 and IR at various fraction sizes on ECM stiffness and fibroblast differenation are studied using MRC-5 fibroblasts in 3-D collagen cultures.