Upregulation of the Oct3/4 network in basal breast cancer is associated with its metastatic potential and shows tissue dependent variability

Adaptive plasticity of Breast Cancer stem cells (BCSCs) is strongly correlated with cancer progression and resistance, leading to a poor prognosis. In this study, we report the expression profile of several pioneer transcription factors of th

RECURRENT SKIN CANCER AFTER BRACHYTHERAPY IN THE MODE OF DOSE HYPOFRACTIONATION AND SINGLE IRRADIATION

Objective: to study the frequency and time of development of recurrent skin cancer after brachytherapy in the mode of dose hypofractionation and single irradiation. Material and Methods: We analysed the results of the examination and treatment of 118 patients with skin cancer stage I-II, of which 60 patients received brachytherapy in the dose hypofractionation mode (group I) and 58 - brachytherapy in a single irradiation mode (group II). Results. As a result of radiation treatment, complete tumor resorption was achieved in 100% of patients in both groups. Within 5 years a relapse was registered in 1 out of 67 (1.5%) exposed lesions in patients from group I; in patients from group II, cancer recurrences were detected in 2 out of 70 (2.85%) tumor foci. Conclusions. Due to the high potential of high-tech brachytherapy for individual choice of dose-time ratio with regard to the anatomical localization of the tumor, its shape and size as well as the nature of the underlying tissues, there is a tendency towards reduction in the number of relapses in patient groups

Sabizabulin, a Potent Orally Bioavailable Colchicine Binding Site Agent, Suppresses HER2+ Breast Cancer and Metastasis

HER2+ breast cancer accounts for 15% of all breast cancer cases. Current frontline therapy for HER2+ metastatic breast cancer relies on targeted antibodies, trastuzumab and pertuzumab, combined with microtubule inhibitors in the taxane class (paclitaxel or docetaxel). It is well known that the clinical efficacy of taxanes is limited by the development of chemoresistance and hematological and neurotoxicities. The colchicine-binding site inhibitors (CBSIs) are a class of promising alternative agents to taxane therapy. Sabizabulin (formerly known as VERU-111) is a potent CBSI that overcomes P-gp-mediated taxane resistance, is orally bioavailable, and inhibits tumor growth and distant metastasis in triple negative breast cancer (TNBC). Herein, we demonstrate the efficacy of sabizabulin in HER2+ breast cancer. In vitro, sabizabulin inhibits the proliferation of HER2+ breast cancer cell lines with low nanomolar IC50 values, inhibits clonogenicity, and induces apoptosis in a concentration-dependent manner. In vivo, sabizabulin inhibits breast tumor growth in the BT474 (ER+/PR+/HER2+) xenograft model and a HER2+ (ER-/PR-) metastatic patient-derived xenograft (PDX) model, HCI-12. We demonstrate that sabizabulin is a promising alternative agent to target tubulin in HER2+ breast cancer with similar anti-metastatic efficacy to paclitaxel, but with the advantage of oral bioavailability and lower toxicity than taxanes

HIF-Dependent CKB Expression Promotes Breast Cancer Metastasis, Whereas Cyclocreatine Therapy Impairs Cellular Invasion and Improves Chemotherapy Efficacy

The oxygen-responsive hypoxia inducible factor (HIF)-1 promotes several steps of the metastatic cascade. A hypoxic gene signature is enriched in triple-negative breast cancers (TNBCs) and is correlated with poor patient survival. Inhibiting the HIF transcription factors with small molecules is challenging; therefore, we sought to identify genes downstream of HIF-1 that could be targeted to block invasion and metastasis. Creatine kinase brain isoform (CKB) was identified as a highly differentially expressed gene in a screen of HIF-1 wild type and knockout mammary tumor cells derived from a transgenic model of metastatic breast cancer. CKB is a cytosolic enzyme that reversibly catalyzes the phosphorylation of creatine, generating phosphocreatine (PCr) in the forward reaction, and regenerating ATP in the reverse reaction. Creatine kinase activity is inhibited by the creatine analog cyclocreatine (cCr). Loss- and gain-of-function genetic approaches were used in combination with cCr therapy to define the contribution of CKB expression or creatine kinase activity to cell proliferation, migration, invasion, and metastasis in ER-negative breast cancers. CKB was necessary for cell invasion in vitro and strongly promoted tumor growth and lung metastasis in vivo. Similarly, cyclocreatine therapy repressed cell migration, cell invasion, the formation of invadopodia and lung metastasis. Moreover, in common TNBC cell line models, the addition of cCr to conventional cytotoxic chemotherapy agents was either additive or synergistic to repress tumor cell growth

Correction: The natural compound Jatrophone interferes with Wnt/β-catenin signaling and inhibits proliferation and EMT in human triple-negative breast cancer.

[This corrects the article DOI: 10.1371/journal.pone.0189864.]

Simultaneous multi-organ metastases from chemo-resistant triple-negative breast cancer are prevented by interfering with WNT-signaling

Triple-negative breast cancers (TNBCs), which lack specific targeted therapy options, evolve into highly chemo-resistant tumors that metastasize to multiple organs simultaneously. We have previously shown that TNBCs maintain an activated WNT10B-driven network that drives metastasis. Pharmacologic inhibition by ICG-001 decreases β-catenin-mediated proliferation of multiple TNBC cell lines and TNBC patient-derived xenograft (PDX)-derived cell lines. In vitro, ICG-001 was effective in combination with the conventional cytotoxic chemotherapeutics, cisplatin and doxorubicin, to decrease the proliferation of MDA-MB-231 cells. In contrast, in TNBC PDX-derived cells doxorubicin plus ICG-001 was synergistic, while pairing with cisplatin was not as effective. Mechanistically, cytotoxicity induced by doxorubicin, but not cisplatin, with ICG-001 was associated with increased cleavage of PARP-1 in the PDX cells only. In vivo, MDA-MB-231 and TNBC PDX orthotopic primary tumors initiated de novo simultaneous multi-organ metastases, including bone metastases. WNT monotherapy blocked multi-organ metastases as measured by luciferase imaging and histology. The loss of expression of the WNT10B/β-catenin direct targets HMGA2, EZH2, AXIN2, MYC, PCNA, CCND1, transcriptionally active β-catenin, SNAIL and vimentin both in vitro and in vivo in the primary tumors mechanistically explains loss of multi-organ metastases. WNT monotherapy induced VEGFA expression in both tumor model systems, whereas increased CD31 was observed only in the MDA-MB-231 tumors. Moreover, WNT-inhibition sensitized the anticancer response of the TNBC PDX model to doxorubicin, preventing simultaneous metastases to the liver and ovaries, as well as to bone. Our data demonstrate that WNT-inhibition sensitizes TNBC to anthracyclines and treats multi-organ metastases of TNBC

Analysis of the tf DNA ends.

<p>(A) Automated sequencing of the bacteriophage tf DNA at termini regions. Alternative end-nucleotides are indicated. (B) Results of the primer extension analysis of the 5′-ends in the tf DNA. Nucleotide positions corresponding to the stoppages at the phage DNA ends are indicated with arrows; black arrow for the position corresponding to the major band and gray arrows – position corresponding to minor bands at the left terminus only. (C) Analysis of the termini junction in the circularized tf DNA. Bacteriophage DNA was treated with T4 DNA polymerase and circularized using T4 DNA ligase. The junction region was analyzed by automated sequencing of the corresponding PCR product as described in the text. The junction identified is shown on the chromatogram by a vertical line and the schematic of the ligated genome ends is shown above the chromatogram. (D) Analysis of the 3′-ends in the tf DNA. Denatured tf DNA was treated with TdT enzyme in separate experiments in the presence of either dATP or dTTP and PCR products were obtained using resulting preparations and one phage specific and one poly-dT (poly-dA) specific primer. Chromatograms for all types of experiments are presented with the corresponding sequences shown at the bottom of the figure. Terminal sequences of the phage genome are shown by shading. (E) Structure of the tf DNA ends’ sequences.</p

Putative processing of the tf DNA from concatemer substrate.

<p>Regions on the concatemer containing terminase recognition sequences are boxed with a red box corresponding designating sequences found at the left end of the genome and a green one – at the right. A putative core recognition site for the terminase enzyme is shaded with grey and positions of cuts are indicated by vertical arrows. Palindrome sequences identified within these sites are shown by horizontal arrowed lines.</p