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Mesenchymal stem/stromal cells (MSCs) encompass a heterogeneous population of fibroblastic progenitor cells that reside in multiple tissues around the body. They are endowed with capacities to differentiate into multiple connective tissue lineages, including chondrocytes, adipocytes, and osteoblasts, and are thought to function as trophic cells recruited to sites of injury and inflammation where they contribute to tissue regeneration. In keeping with these roles, MSCs also to home to sites of breast tumorigenesis, akin to their migration to wounds, and participate in tumor stroma formation. Mounting evidence over the past two decades has described the critical regulatory roles for tumor-associated MSCs in various aspects of breast tumor pathogenesis, be it tumor initiation, growth, angiogenesis, tumor microenvironment formation, immune evasion, cancer cell migration, invasion, survival, therapeutic resistance, dissemination, and metastatic colonization. In this review, we present a brief summary of the role of MSCs in breast tumor development and progression, highlight some of the molecular frameworks underlying their pro-malignant contributions, and present evidence of their promising utility in breast cancer therapy. [ABSTRACT FROM AUTHOR]

Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors. Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer. [ABSTRACT FROM AUTHOR]