Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor α, progesterone receptor and human epidermal growth factor receptor 2 (HER2). TNBC patients lack targeted therapies, as they fail to respond to endocrine and anti-HER2 therapy. Prognosis for this aggressive cancer subtype is poor and survival is limited due to the development of resistance to available chemotherapies and resultant metastases. The mechanisms regulating tumor resistance are poorly understood. Here we demonstrate that the G protein-coupled kisspeptin receptor (KISS1R) promotes drug resistance in TNBC cells. KISS1R binds kisspeptins, peptide products of the KISS1 gene and in numerous cancers, this signaling pathway plays anti-metastatic roles. However, in TNBC, KISS1R promotes tumor invasion. We show that KISS1 and KISS1R mRNA and KISS1R protein are upregulated in TNBC tumors, compared to normal breast tissue. KISS1R signaling promotes drug resistance by increasing the expression of efflux drug transporter, breast cancer resistance protein (BCRP) and by inducing the activity and transcription of the receptor tyrosine kinase, AXL. BCRP and AXL transcripts are elevated in TNBC tumors, compared to normal breast, and TNBC tumors expressing KISS1R also express AXL and BCRP. Thus, KISS1R represents a potentially novel therapeutic target to restore drug sensitivity in TNBC patients.

Key pointsr Postnatal intake of a high saturated fat/high sugar diet, the Western diet (WD), is a risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development.r We demonstrate that suboptimal in utero conditions resulting in LBW are associated with changes in hepatic profibrotic genes in conjunction with minimal liver fibrosis in young non-overweight adult guinea pigs.r Our results also indicate that WD promotes liver steatosis, enhanced expression of hepatic genes and proteins of the proinflammatory, profibrotic, cell death and collagen deposition pathways in conjunction with mild hepatic fibrosis.r Our data highlight that pathways responsible for the initiation of a profibrotic state and ultimately hepatic fibrosis appear different depending upon the insult, an in utero-induced LBW outcome or a postnatal WD exposure.Abstract Postnatal intake of an energy dense diet, the Western diet (WD), is a strong risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development. We assessed the independent and possible synergistic effects of placental insufficiency-induced LBW and postnatal WD consumption on liver fibrosis in early adulthood, with a specific focus on changes in inflammation and apoptosis pathways in association with fibrogenesis. Male LBW (uterine artery ablation) and normal birth weight (NBW) guinea pig pups were fed either a control diet (CD) or WD from weaning to 150 days. Significant steatosis, mild lobular inflammation, apoptosis and mild stage 1 fibrosis (perisinusoidal or portal) were evident in WD-fed offspring (NBW/WD and LBW/WD). In LBW/CD versus NBW/CD offspring, increased transforming growth factor-beta 1 and matrix metallopeptidase mRNA and sma-and Mad-related protein 4 (SMAD4) were present in conjunction with minimal stage 1 portal fibrosis. Further, connective tissue growth factor mRNA was increased and miR-146a expression decreased in LBW offspring, irrespective of diet. Independent of birth weight, WD-fed offspring exhibited increased expression of fibrotic genes as well as elevated inflammatory and apoptotic markers. Moreover, the augmented expression of collagen, type III, alpha 1 and tumor necrosis factor-alpha was associated with increased recruitment of RNA polymerase II and enhanced histone acetylation (K9) to their respective promoters. These data support a role for both LBW and postnatal WD as factors contributing to hepatic fibrosis development in offspring through distinct pathways.

Topoisomerase II (TopoII) plays a critical role in the processes of replication, transcription, and decantenation in the cell and is an important chemotherapeutic target in the treatment of small cell lung cancer (SCLC). Current treatment strategies for SCLC employ the use of topoII poisons which stabilize the topoII-DNA transient covalent complex, inducing double stranded DNA damage and cellular death via apoptosis in cancer cells. Despite their effectiveness the topoII poisons are known to induce secondary malignancies in a small population of patients, stimulating the search for new compounds with less toxicity. Recently a small library of substituted 9-aminoacridine derivatives was discovered that displayed topoII catalytic inhibitory properties. In this work we assess their ability to inhibit proliferation and induce cellular death in SCLC. The results indicate effective inhibition of cellular proliferation at EC(50) values in the low μM range. Western blot analysis of p62/LC3 levels, the AKT/mTOR pathway, and the ERK1/2 pathway indicate that autophagy is occurring as the primary mechanism of cell death; furthermore, the Guava Nexin and caspase 3/7 activation assays indicate that apoptosis does not occur. While it is unlikely that the active concentration of these compounds could be achieved in vivo, they show great promise for the use and effectiveness of acridine derivatives in the treatment of SCLC in the future.

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