If You Don't Look, You Won't See: Intravital Multiphoton Imaging of Primary and Metastatic Breast Cancer

A fundamental hallmark of cancer is progression to metastasis and the growth of breast cancer metastases in lung, bone, liver and/or brain causes fatal complications. Unfortunately, the cellular and biochemical mechanisms of the metastatic process remain ill-defined. Recent application of intravital multiphoton microscopy (MP-IVM) to image fluorescently labeled cells in mouse models of cancer has allowed dynamic observation of this multi-step process at the cellular and subcellular levels. In this article, we discuss the use of MP-IVM in studies of breast cancer metastasis, as well as surgical techniques for exposing tumors prior to imaging. We also describe a versatile multiphoton microscope for imaging tumor-stroma interaction

European Network of Breast Development and Cancer turned 10 years: a growing family of mammary gland researchers

The European Network for Breast Development and Cancer (ENBDC), a worldwide network (http://www.enbdc.org/), celebrated its tenth anniversary with a fantastic meeting last March 15-17, 2018 in Weggis with 76 attendees

Methods in Mammary Gland Development and Cancer: the second ENDBC meeting - intravital imaging, genomics, modeling and metastasis

The second meeting of the European Network for Breast Development and Cancer (ENBDC) on 'Methods in Mammary Gland Development and Cancer' was held in April 2010 in Weggis, Switzerland. The focus was on genomics and bioinformatics, extracellular matrix and stroma-epithelial cell interactions, intravital imaging, the search for metastasis founder cells and mouse models of breast cancer

Complexity galore:3D cultures, biomechanics and systems medicine at the eighth ENBDC workshop "Methods in Mammary Gland Development and Cancer"

The ENBDC workshop “Methods in Mammary Gland Development and Cancer” is an established international forum to showcase the latest technical advances in the field. The eighth meeting focused on emerging concepts and technologies for studying normal and neoplastic breast development

Glucocorticoids promote breast cancer metastasis

Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy(1-3). Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade(4), remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.Peer reviewe

Can phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibition ERase them all?

Seventy percent of breast tumors are estrogen receptor (ER) positive. Although endocrine therapy is successful for the majority of patients with ER-positive tumors, approximately 30% show de novo or acquired resistance and the underlying molecular mechanisms and biomarkers that predict such resistance remain elusive. Two recent papers report that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway produces resistance to tamoxifen. This raises the possibility that combining endocrine therapy and PI3K inhibition may be more effective than monotherapy for treating ER-positive breast tumors, either as first-line therapy for tumors with high PI3K activity or after the development of resistance to endocrine therapy

PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer.

The protein tyrosine phosphatase SHP2 activates oncogenic pathways downstream of most receptor tyrosine kinases (RTK) and has been implicated in various cancer types, including the highly aggressive subtype of triple-negative breast cancer (TNBC). Although allosteric inhibitors of SHP2 have been developed and are currently being evaluated in clinical trials, neither the mechanisms of the resistance to these agents, nor the means to circumvent such resistance have been clearly defined. The PI3K signaling pathway is also hyperactivated in breast cancer and contributes to resistance to anticancer therapies. When PI3K is inhibited, resistance also develops for example via activation of RTKs. We therefore assessed the effect of targeting PI3K and SHP2 alone or in combination in preclinical models of metastatic TNBC. In addition to the beneficial inhibitory effects of SHP2 alone, dual PI3K/SHP2 treatment decreased primary tumor growth synergistically, blocked the formation of lung metastases, and increased survival in preclinical models. Mechanistically, transcriptome and phospho-proteome analyses revealed that resistance to SHP2 inhibition is mediated by PDGFRβ-evoked activation of PI3K signaling. Altogether, our data provide a rationale for co-targeting of SHP2 and PI3K in metastatic TNBC

It's all in the details: methods in breast development and cancer

The inaugural European Network for Breast Development and Cancer (ENBDC) meeting on 'Methods in Mammary Gland Development and Cancer' was held in Weggis, Switzerland last April. The goal was to discuss the details of techniques used to study mammary gland biology and tumourigenesis. Highlights of this meeting included the use of four-colour fluorescence for protein co-localisation in tissue microarrays, genome analysis at single cell resolution, technical issues in the isolation of normal and tumour stem cells, and the use of mouse models and mammary gland transplantations to elucidate gene function in mammary development and to study drug resistance in breast cancer