Breast cancer is associated with the second highest cancer-associated deaths worldwide. Therefore, understanding the key events that determine breast cancer progression, modulation of the tumor-microenvironment and metastasis, which is the main cause of cancer-associated death, are of great importance. The mammary specific polyomavirus middle T antigen overexpression mouse model (MMTV-PyMT), first published in 1992, is the most commonly used genetically engineered mouse model (GEMM) for cancer research. Mammary lesions arising in MMTV-PyMT mice follow similar molecular and histological progression as human breast tumors, making it an invaluable tool for cancer researchers and instrumental in understanding tumor biology. In this review, we will highlight key studies that demonstrate the utility of PyMT derived GEMMs in understanding the molecular basis of breast cancer progression, metastasis and highlight its use as a pre-clinical tool for therapeutic discovery.
Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcome, yet the underlying mechanisms are incompletely understood. Here, we have shown that deleting c-Src in a genetically engineered model mimicking the Luminal B molecular subtype of breast cancer abrogates the activity of Forkhead Box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylates FOXM1 on two tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2-M cell cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of Luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2-M cell cycle arrest and apoptosis, blocked tumor progression and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and showed that the expression of FOXM1 target genes predicts poor outcome and associates with the Luminal B subtype, which responds poorly to approved therapies. These findings have revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.
Breast cancer remains a significant clinical concern affecting millions of women worldwide. Immunotherapy is a rapidly growing drug class that has revolutionized cancer treatment but remains marginally successful in breast cancer. The success of immunotherapy is dependent on the baseline immune responses as well as removing the brakes off pre-existing anti-tumor immunity. In this review, we summarize the different types of immune microenvironment observed in breast cancer as well as provide approaches to target these different immune subtypes. Such approaches have demonstrated pre-clinical success and are currently under clinical evaluation. The impact of combination of these approaches with already approved chemotherapies and immunotherapies may improve patient outcome and survival.
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