Breast cancer is the most common cancer among women, affecting approximately one million women worldwide. Understanding the cellular and microenvironmental changes that contribute to breast cancer initiation and progression will allow the most effective treatment regimens to be discovered. The studies described here began with normal human mammary epithelial cells (HMECs) obtained from reduction mammoplasties. The stepwise addition of specific genetic alterations created a transformation model that mimics the progression of breast cancer. Constitutive cyclin D1/cyclin-dependent kinase (CDK) activity promotes the hyperphosphorylation and inactivation of the RB family of tumor suppressor proteins. To study the role of wild-type p53 and its ability to be reactivated inbreast cancers, a cyclin D1/CDK fusion protein (D1/CDK) was expressed in immortalized HMECs allowing the cells to grow anchorage-independently, a hallmark of transformation. Importantly, the D1/CDK-mediated transformation occurred even in the presence of wild-type p53, providing a model to study p53 reactivation by the therapeutic compound Nutlin-3, an HDM2 antagonist. Interestingly, p53 could be activated by treatment with Nutlin-3, leading to a p53-dependent, but RB-independent growth arrest through the stable down-regulation of critical cell cycle proteins. Since a significant percentage of breast cancers overexpress cyclin D1 and have constitutive CDK activity, this study provides important information regarding the efficacy of p53 reactivation in such tumors. Further work to reveal tumor suppressive mechanisms which are overcome during tumorigenesis examined the effect of the cytokine Oncostatin M (OSM) on normal and transformed HMECs, uncovering a regulatory switch that can suppress or promote growth. In HMECs, OSM induced a STAT3-dependent, p53-independent growth arrest. However, the overexpression of c-MYC not only prevented OSM-induced growth arrest but promoted transformation. Therefore, OSM induces a growth arrest in normal HMECs, but can promote transformation once certain tumor suppressive mechanisms are disabled. Given the role of OSM in stromal cell signaling this work implicates microenvironmental factors as an important influence on breast cancer progression. The results presented here have identified novel growth arrest pathways that can aid in the identification of new therapeutic targets and advance our understanding of breast cancer development and treatment.