Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell–cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.

The docking protein p140Cap negatively regulates tumour cell features. Its relevance on breast cancer patient survival, as well as its ability to counteract relevant cancer signalling pathways, are not fully understood. Here we report that in patients with ERBB2-amplified breast cancer, a p140Cap-positive status associates with a significantly lower probability of developing a distant event, and a clear difference in survival. p140Cap dampens ERBB2-positive tumour cell progression, impairing tumour onset and growth in the NeuT mouse model, and counteracting epithelial mesenchymal transition, resulting in decreased metastasis formation. One major mechanism is the ability of p140Cap to interfere with ERBB2-dependent activation of Rac GTPase-controlled circuitries. Our findings point to a specific role of p140Cap in curbing the aggressiveness of ERBB2-amplified breast cancers and suggest that, due to its ability to impinge on specific molecular pathways, p140Cap may represent a predictive biomarker of response to targeted anti-ERBB2 therapies.

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Cholesterol is an essential lipid primarily synthesized in the liver through the mevalonate pathway. Besides being a precursor of steroid hormones, bile acid, and vitamin D, it is an essential structural component of cell membranes, is enriched in membrane lipid rafts, and plays a key role in intracellular signal transduction. The lipid homeostasis is finely regulated end appears to be impaired in several types of tumors, including breast cancer. In this review, we will analyse the multifaceted roles of cholesterol and its derivatives in breast cancer progression. As an example of the bivalent role of cholesterol in the cell membrane of cancer cells, on the one hand, it reduces membrane fluidity, which has been associated with a more aggressive tumor phenotype in terms of cell motility and migration, leading to metastasis formation. On the other hand, it makes the membrane less permeable to small water-soluble molecules that would otherwise freely cross, resulting in a loss of chemotherapeutics permeability. Regarding cholesterol derivatives, a lower vitamin D is associated with an increased risk of breast cancer, while steroid hormones, coupled with the overexpression of their receptors, play a crucial role in breast cancer progression. Despite the role of cholesterol and derivatives molecules in breast cancer development is still controversial, the use of cholesterol targeting drugs like statins and zoledronic acid appears as a challenging promising tool for breast cancer treatment.

Neuroblastoma is the most common extra-cranial pediatric solid tumor, responsible for 13-15% of pediatric cancer death. Its intrinsic heterogeneity makes it difficult to target for successful therapy. The adaptor protein p140Cap/SRCIN1 negatively regulates tumor cell features and limits breast cancer progression. This study wish to assess if p140Cap is a key biological determinant of neuroblastoma outcome. RNAseq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In highrisk patients, CGH+SNP microarray analysis of primary neuroblastoma identifies SRCIN1 as frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional experiments show that p140Cap negatively regulates Src and STAT3 signaling, affects anchorage-independent growth and migration, in vivo tumor growth and spontaneous lung metastasis formation. p140Cap also increases sensitivity of neuroblastoma cells to doxorubicin and etoposide treatment, as well as to a combined treatment with chemotherapy drugs and Src inhibitors. Our functional findings point to a causal role of p140Cap in curbing the aggressiveness of neuroblastoma, due to its ability to impinge on specific molecular pathways, and to sensitize cells to therapeutic treatment. This study provides the first evidence that the SRCIN1/p140Cap adaptor protein is a key player in neuroblastoma as a new independent prognostic marker for patient outcome and treatment. Altogether, these data highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment. Background Neuroblastoma (NB) is a complex disease with different outcome, responsible for a large proportion of cancer death in childhood [1, 2]. Primary NB originate from genetic abnormalities in neural crest-derived sympathoadrenal cells [1]. The International Neuroblastoma Staging System (INSS) defines 5 stages of NB progression [3], from Stages 1 and 2 (localized tumor, without lymph nodes involvement) to Stage 3 and Stage 4 (metastatic disease, with dissemination in distant organs). Stage 4S specifies a metastatic disease in children under the age of 1 year, which may undergo spontaneous regression usually associated with 90% survival rate at 5 years. The therapeutic intervention in NB (surgery for stages 1 and 2, and multipleagent chemotherapy [4, 5]), does not increase substantially