<p>Breast cancer remains the leading cause of death among females worldwide. While systemic therapy for breast cancer may work effectively in the early phases, for more than 10% of primary and 50% of metastatic cases, the disease eventually progresses, resisting treatments. To overcome this issue, recognizing markers of resistance as early as possible is critical. However, the underlying mechanisms of resistance remains elusive. The influence of microenvironmental factors of the extracellular matrix (ECM) on tumor behavior has been revealed relatively recently and increased stiffness of ECM is associated with cancer progression. Additionally, impacts of other matrix components such as non-neoplastic epithelial cells (that may constitute an important portion of the tumor microenvironment -TME) are suspected to influence tumors but they have not been investigated in detail. Besides, it is not known whether the response to increasing stiffness depends on the subtypes of breast cancer. Here, using breast models in 3D cell culture we have shown that the non-neoplastic epithelial compartment can influence the effect of matrix stiffness even for tumors recognized as highly aggressive. The degree of tumor aggressiveness recognizable via tumor architecture is associated with a differential behavior when ECM stiffness changes. In a 3D microenvironmental context, which provides an optimal level of constraints for tumors to display their phenotype, we report stiffness and paracrine influence impact on cisplatin-mediated cytotoxicity, which correlates with distinct nuclear morphometry and distribution pattern associated with population heterogeneity. The response pattern varies across cell lines representing higher and lower levels of aggressiveness in the basal-like subtypes of breast cancer. Our results also highlight the need for integrating biochemical and physical components of the TME in future designs of <i>in vitro</i> drug screening platforms.</p>