intraductal-delivery-x-ray-visualization-ethanol-based-ablative

Intraductal Delivery and X-ray Visualization of Ethanol-Based Ablative Solution for Prevention and Local Treatment of Breast Cancer in Mouse Models

Breast cancer is the most prevalent cancer and the second-leading cause of cancer-related death for women in the USA. For high-risk women, prophylactic ...

van andel research institute

Miltenyi Biotec

Van Andel Research Institute

Breast cancer is a complex and heterogeneous disease. Signaling by estrogen receptor (ER), progesterone receptor (PR), and/or human EGF-like receptor 2 (HER2) is a main driver in the development and progression of a large majority of breast tumors. Molecular characterization of primary tumors has identified major subtypes that correlate with ER/PR/HER2 status, and also subgroup divisions that indicate other molecular and cellular features of the tumors. While some of these research findings have been incorporated into clinical practice, several challenges remain to improve breast cancer management and patient survival, for which the integration of novel biomarkers into current practice should be beneficial. microRNAs (miRNAs) are a class of short non-coding regulatory RNAs with an etiological contribution to breast carcinogenesis. miRNA-based diagnostic and therapeutic applications are rapidly emerging as novel potential approaches to manage and treat breast cancer. Rapid technological development enables specific and sensitive detection of individual miRNAs or the entire miRNome in tissues, blood, and other biological specimens from breast cancer patients. This review focuses on recent miRNA research and its potential to address unmet clinical needs and challenges. The four sections presented discuss miRNA findings in the context of the following clinical challenges: biomarkers for early detection; prognostic and predictive biomarkers for treatment decisions using targeted therapies against ER and HER2; diagnostic and prognostic biomarkers for subgrouping of triple-negative breast cancer, for which there are currently no targeted therapies; and biomarkers for monitoring and characterization of metastatic breast cancer. The review concludes with a critical analysis of the current state of miRNA breast cancer research and the need for further studies using large patient cohorts under well-controlled conditions before considering the clinical implementation of miRNA biomarkers. 

Critical analysis of the potential for microRNA biomarkers in breast cancer management.

Prophylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant.

Ductal tree ablation by local delivery of ethanol prevents tumor formation in an aggressive mouse model of breast cancer.

The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven p53-deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor-restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR-21 loss. Stromal miR-21 activity was required for induction of tumor-restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in The Cancer Genome Atlas PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor-suppressive function of miR-21 in in vivo PDAC models. These results have important clinical implications for anti-miR-21-based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell-intrinsic role of miR-21 in cancer-associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR-21 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.

Jennifer J. Westerhuis

van andel research institute

Intraductal Delivery and X-ray Visualization of Ethanol-Based Ablative Solution for Prevention and Local Treatment of Breast Cancer in Mouse Models