Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation

Mouse models of breast cancer metastasis

Metastatic spread of cancer cells is the main cause of death of breast cancer patients, and elucidation of the molecular mechanisms underlying this process is a major focus in cancer research. The identification of appropriate therapeutic targets and proof-of-concept experimentation involves an increasing number of experimental mouse models, including spontaneous and chemically induced carcinogenesis, tumor transplantation, and transgenic and/or knockout mice. Here we give a progress report on how mouse models have contributed to our understanding of the molecular processes underlying breast cancer metastasis and on how such experimentation can open new avenues to the development of innovative cancer therapy

Py2T murine breast cancer cells, a versatile model of TGFβ-induced EMT in vitro and in vivo.

INTRODUCTION: Increasing evidence supports a role of an epithelial to mesenchymal transition (EMT) process in endowing subsets of tumor cells with properties driving malignant tumor progression and resistance to cancer therapy. To advance our understanding of the underlying mechanisms, we sought to generate a transplantable cellular model system that allows defined experimental manipulation and analysis of EMT in vitro and at the same time recapitulates oncogenic EMT in vivo. METHODOLOGY/RESULTS: We have established a stable murine breast cancer cell line (Py2T) from a breast tumor of an MMTV-PyMT transgenic mouse. Py2T cells display a metastable epithelial phenotype characterized by concomitant expression of luminal and basal cytokeratins and sheet migration. Exposure of Py2T cells to transforming growth factor β (TGFβ) in vitro induces reversible EMT accompanied by downregulation of E-cadherin and upregulation of mesenchymal markers, including EMT transcription factors, and a gain in single cell motility and invasiveness. Py2T cells give rise to tumors after orthotopic injection into syngeneic FVB/N mice. Notably, transplantation of epithelial Py2T cells results in the formation of invasive primary tumors with low to absent E-cadherin expression, indicating that the cells undergo EMT-like changes in vivo. This process appears to at least in part depend on TGFβ signaling, since tumors formed by Py2T cells expressing a dominant-negative version of TGFβ receptor widely maintain their epithelial differentiation status. CONCLUSIONS/SIGNIFICANCE: Together, the data demonstrate that the Py2T cell line represents a versatile model system to study the EMT process in vitro and in vivo. The observation that Py2T cells give rise to tumors and collectively undergo EMT-like changes in vivo highlights the suitability of the Py2T model system as a tool to study tumor-related EMT. In particular, Py2T cells may serve to corroborate recent findings relating EMT to cancer cell stemness, to therapy resistance and to tumor recurrence