Breast cancer (BC) and endocrine resistance to chemotherapy are challenging problems where angiogenesis plays fundamental roles. Thus, targeting of VEGFR-2 signalling pathway has been an attractive approach. In this study, we synthesised a new sorafenib analogue, thieno[2,3-d]pyrimidine based urea derivative, KM6. It showed 65% inhibition of VEGF2 tyrosine kinase activity and demonstrated a potential antitumor activity in TAM-resistant, LCC2, and its parental MCF7 BC cells. KM6 retained the sensitivity of LCC2 through upregulation of key enzymes of apoptosis and proteins of cell death including caspases 3, 8, 9, P53, BAX/BCL-2 ratio and LDH in media. It downregulated mRNA expression of Ki-67, survivin, Akt, and reduced levels of ROS and glucose uptake. Moreover, KM6 reduced the levels of inflammation markers PGE2, COX2, IL-1β and IL6 and metastasis markers MMP-2 and MMP-9. In conclusion, KM6 is a promising compound for ER + and TAM-resistant BC with many potential antitumor and polypharmacological mechanisms. Graphical Abstract

The clinical usage of doxorubicin (DOX) is hampered due to cardiomyopathy. Studies reveal that estrogen (E2) modulates DOX-induced cardiotoxicity. Yet, the exact mechanism is unclear. The objective of the current study is to evaluate the influence of E2 and more specifically its metabolite 2-methoxyestradiol (2ME) on cardiac remodeling and the reprogramming of cardiac metabolism in rats subjected to DOX cardiotoxicity. Seventy-two female rats were divided into groups. Cardiotoxicity was induced by administering DOX (2.5 mg/kg three times weekly for 2 weeks). In some groups, the effect of endogenous E2 was abolished by ovariectomy (OVX) or by using the estrogen receptor (ER) blocker Fulvestrant (FULV). The effect of administering exogenous E2 or 2ME in the OVX group was studied. Furthermore, the influence of entacapone (COMT inhibitor) on induced cardiotoxicity was investigated. The evaluated cardiac parameters included ECG, histopathology, cardiac-related enzymes (creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH)), and lipid profile markers (total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL)). The expression levels of key metabolic enzymes (glucose transporter-4 (GLUT4) and carnitine palmitoyltransferase-1B (CPT-1B)) were assessed. Our results displayed that co-treatment of E2 and/or 2ME with DOX significantly reduced DOX-induced cardiomyopathy and enhanced the metabolism of the heart through the maintenance of GLUT4 and CPT-1B enzymes. On the other hand, co-treatment of DOX with OVX, entacapone, or FULV increased the toxic effect of DOX by further reducing these important metabolic enzymes. E2 and 2ME abrogate DOX-induced cardiomyopathy partly through modulation of GLUT 4 and CPT-1B enzymes. Graphical Abstract

Purpose: Androgen receptor (AR) is often expressed in breast cancer, but its role in estrogen receptor positive (ER+) type is controversial. Although AR and its splicing variant 7 (ARV7) play a role in the pathobiology of breast cancer, the precise mechanisms are not fully understood. Therefore, the aim of the current study is to determine the influence of the blockers of AR (Enzalutamide) and ARV7 (EPI-001) on metastasis and epithelial to mesenchymal transition (EMT) in T47D, an ER+ breast cancer cell line. Methods: T47D cells were cultured/treated with Enzalutamide or EPI-001; cytotoxicity and cell cycle analysis were determined using Sulphorhodamine-B (SRB) assay and Flowcytometry analysis, respectively, whereas metastasis was assessed by the Scratch wound healing assay. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of AR, ARV7, C-myc, N-Cadherin, E-Cadherin, NF-κB, ROCK1 and 2 and Western blot was used for evaluating the protein expression of cyclin dependent kinases (CDK4, CDK6, Cyclin E), Fibronectin, vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP2 and MMP9). Results: Our results indicated that treatment with Enzalutamide or EPI-001 didn't significantly affect cell proliferation of T47D. However, cells were arrested at S-phase accompanied by a decline in CDK4, CDK6, Cyclin E and metastasis. Fibronectin, VEGF, MMP2, MMP9, ROCK1 and ROCK2 proteins were downregulated. C-myc and NF-κB levels were declined by EPI-001, but not Enzalutamide.Conclusion: Blocking AR/ARV7 has no effect on cell proliferation, but decreases metastasis by regulating key markers and processes involved in EMT in ER+ breast cancer cells.