Exploring new pathways in endocrine-resistant breast cancer.

The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors.

Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.

An shRNA-based screen of splicing regulators identifies SFRS3 as a negative regulator of IL-1ß secretion.

The generation of diversity and plasticity of transcriptional programs are key components of effective vertebrate immune responses. The role of Alternative Splicing has been recognized, but it is underappreciated and poorly understood as a critical mechanism for the regulation and fine-tuning of physiological immune responses. Here we report the generation of loss-of-function phenotypes for a large collection of genes known or predicted to be involved in the splicing reaction and the identification of 19 novel regulators of IL-1ß secretion in response to E. coli challenge of THP-1 cells. Twelve of these genes are required for IL-1ß secretion, while seven are negative regulators of this process. Silencing of SFRS3 increased IL-1ß secretion due to elevation of IL-1ß and caspase-1 mRNA in addition to active caspase-1 levels. This study points to the relevance of splicing in the regulation of auto-inflammatory diseases.

RNA interference knockdown of hU2AF35 impairs cell cycle progression and modulates alternative splicing of Cdc25 transcripts.

U2AF is a heterodimeric splicing factor composed of a large (U2AF65) and a small (U2AF35) subunit. In humans, alternative splicing generates two U2AF35 variants, U2AF35a and U2AF35b. Here, we used RNA interference to specifically ablate the expression of each isoform in HeLa cells. Our results show that knockdown of the major U2AF35a isoform reduced cell viability and impaired mitotic progression, leading to accumulation of cells in prometaphase. Microarray analysis revealed that knockdown of U2AF35a affected the expression level of approximately 500 mRNAs, from which >90% were underrepresented relative to the control. Among mRNAs underrepresented in U2AF35a-depleted cells we identified an essential cell cycle gene, Cdc27, for which there was an increase in the ratio between unspliced and spliced RNA and a significant reduction in protein level. Furthermore, we show that depletion of either U2AF35a or U2AF35b altered the ratios of alternatively spliced isoforms of Cdc25B and Cdc25C transcripts. Taken together our results demonstrate that U2AF35a is essential for HeLa cell division and suggest a novel role for both U2AF35 protein isoforms as regulators of alternative splicing of a specific subset of genes.