The MyD88 inhibitor TJ-M2010-2 suppresses proliferation, migration and invasion of breast cancer cells by regulating MyD88/GSK-3ß and MyD88/NF-κB signalling pathways.

MyD88 has been implicated in the tumourigenesis, metastasis and recurrence of breast cancer (BC). Here we utilized TJ-M2010-2 (TJ), an inhibitor of MyD88 homodimerimerization, and siMyD88 to suppress the function of MyD88 in MCF-7 and MDA-MB-231 cells. BC cells were treated in vitro and xenografted into nude mice to generate a model in vivo. TJ inhibited BC cell growth by impeding proliferation rather than by promoting apoptosis in vitro. Additionally, TJ and siMyD88 significantly attenuated cell migration and invasion, inhibited EMT-like progression and reduced cytokine (IL-6, IL-8, TGF-ß1 and TNF-α) secretion induced by LPS. In vivo, TJ significantly hindered tumour growth in mice. Notably, TJ also decreased the secretion of IL-6, IL-8, TGF-ß1, and TNF-α and M2 macrophage infiltration in the tumour microenvironment. The expression of MyD88, TRAF6, NF-κB p65, Snail, MMP-2, MMP-9, p-GSK-3ß and p-Akt was significantly downregulated by TJ in BC cells and tumour tissues. Collectively, these results suggest that a MyD88 inhibitor (TJ) may be a promising therapeutic modality for treating BC patients.

Intraductal photothermal ablation: a noninvasive approach for early breast cancer treatment and prevention.

Background: Innovative treatment strategies for early-stage breast cancer (BC) are urgently needed. Tumors originating from mammary ductal cells present an opportunity for targeted intervention. Methods: We explored intraductal therapy via natural nipple openings as a promising non-invasive approach for early BC. Using functional Near-infrared II (NIR-II) nanomaterials, specifically NIR-IIb quantum dots conjugated with Epep polypeptide for ductal cell targeting, we conducted in situ imaging and photothermal ablation of mammary ducts. Intraductal administration was followed by stimulation with an 808 nm laser. Results: This method achieved precise ductal destruction and heightened immunological responses in the microenvironment. The technique was validated in mouse models of triple-negative BC and a rat model of ductal carcinoma in situ, demonstrating promising therapeutic potential for localized BC treatment and prevention. Conclusion: Our study demonstrated the effectiveness of NIR-II nanoprobes in guiding non-invasive photothermal ablation of mammary ducts, offering a compelling avenue for early-stage BC therapy.

In situ Injection of pH- and Temperature-Sensitive Nanomaterials Increases Chemo-Photothermal Efficacy by Alleviating the Tumor Immunosuppressive Microenvironment.

Purpose: Triple-negative breast cancer (TNBC) is challenging to treat with traditional "standard of care" therapy due to the lack of targetable biomarkers and rapid progression to distant metastasis. Methods: We synthesized a novel combination regimen that included chemotherapy and photothermal therapy (PTT) to address this problem. Here, we tested a magnetic nanosystem (MNs-PEG/IR780-DOX micelles) loaded with the near-infrared (NIR) photothermal agent IR780 and doxorubicin (DOX) to achieve chemo-photothermal and boost antitumor immunity. Intraductal (i.duc) administration of MNs-PEG/IR780-DOX could increase the concentration of the drug in the tumor while reducing systemic side effects. Results: We showed more uptake of MNs-PEG/IR780-DOX by 4T1-luc cells and higher penetration in the tumor. MNs-PEG/IR780-DOX exhibited excellent photothermal conversion in vivo and in vitro. The release of DOX from MNs-PEG/IR780-DOX is pH- and temperature-sensitive. Facilitated by i.duc administration, MNs-PEG/IR780-DOX displayed antitumor effects and prevented distant organs metastasis under NIR laser (L) irradiation and magnetic field (MF)while avoiding DOX-induced toxicity. More importantly, MNs-PEG/IR780-DOX alleviated tumor immunosuppressive microenvironment by increasing tumor CD8+ T cells infiltration and reducing the proportion of myeloid-derived suppressor cells (MDSCs) and Tregs. Conclusion: Intraductal administration of pH- and temperature-sensitive MNs-PEG/IR780-DOX with L and MF had the potential for achieving minimally invasive, targeted, and accurate treatment of TNBC.

Intraductal administration of N-methyl-N-nitrosourea as a novel rodent mammary tumor model.

BACKGROUND: Chemically induced animal models of breast cancer (BC) using N-methyl-N-nitrosourea (MNU) have been widely used in preclinical research. The conventional approach entails intraperitoneal (i.p) or intravenous injection of a carcinogen, leading to tumor induction at unpredictable locations. This study aimed to establish a modified MNU-induced rat mammary tumor model using intraductal (i.duc) administration and to evaluate its biological behavior, morphology, and response to chemotherapy drugs. METHODS: In a pilot experiment, female Sprague-Dawley (SD) rats were injected with either i.duc MNU or vehicle to test the feasibility of this approach. We explored the appropriate dosage for stable tumor formation in pubescent female SD rats by testing a single i.duc dose of MNU (0.5, 1.0 and 2.0 mg) or vehicle. RESULTS: An i.duc injection of 20 µL (1 mg/per duct) MNU in the fourth rat mammary gland induced stable carcinomas in situ. Immunohistochemical (IHC) analysis showed positive expression of estrogen receptor (ER), negative expression of human epidermal growth factor receptor 2 (Her-2), and low expression of Ki-67. Histopathology revealed atypical hyperplasia in the mammary gland 4 weeks after carcinogen injection, developing into carcinoma in situ 5-6 weeks after treatment, with loss of α-SMA and calponin expressions during tumor progression. Albumin-bound paclitaxel (nab-PTX) was injected i.duc and intravenously (i.v) 5 weeks after administration of MNU. The tumor growth rate of the nab-PTX i.duc-treated group was lower than in the i.v and control groups. The number of TUNEL-positive apoptotic cells was significantly higher in the nab-PTX i.duc-treated group. CONCLUSIONS: Using i.duc MNU (20 µL, 1 mg) to establish a rat mammary tumor model resulted in a predictable location in the rat mammary gland and exhibited better consistency; i.duc administration of nab-PTX permitted a smaller drug dose, but produced a better drug response, than i.v injection.

Relationships of hepatitis B virus infection with clinicopathological features in breast cancer and survival outcomes in central China.

BACKGROUND: The purpose of this study was to determine the effect of hepatitis B virus (HBV) infection on the clinicopathological features and survival outcomes of breast cancer (BC) patients. METHODS: Patients diagnosed with BC at the Breast and Thyroid Center, Renmin Hospital, Wuhan University between January 2013 and December 2017 were included in the study. Among these patients, 100 (8.4%) were infected with HBV (case group), while 237 (19.9%) had never come into contact with HBV (control group). Chi-square tests for analyses of clinicopathological features, Kaplan-Meier survival analyses, the log-rank test for disease-free survival (DFS) between the case and control group, along with the factors correlated with prognosis, were evaluated using univariate and multivariate analyses. RESULTS: The median follow-up of the patients in the case and control groups was 34.5 months. The clinicopathological features revealed that patients with HBV tended to have smaller tumors compared with the control group (case vs. control: 53.0% vs. 65.8%, P<0.05). In addition, more grade 3 tumors were observed in patients with HBV (case vs. control: 55.0% vs. 37.6%, P<0.01). The 3-year DFS was 94.3% in the case group and 89.4% in the control group patients (P=0.212). In multivariate analysis, nodal status [hazard ratio (HR) =5.033, P=0.003] and estrogen receptor (ER) status (HR =0.216, P=0.023) were both independent prognostic risk factors for DFS. However, HBV infection had no association with the DFS of BC. CONCLUSIONS: BC patients in central China have a higher incidence rate of HBV infection than the general population does. BC patients with chronic HBV infection tend to have an earlier tumor stage and higher histological grade, but there is no association with the DFS of BC.

The risk of developing acute non-lymphocytic leukemia in women with breast cancer.

BACKGROUND: This study had the purpose of examining the incidences, risk factors, and survival outcome of developing subsequent acute non-lymphocytic leukemia (ANLL) among a large group of breast cancer survivors. METHODS: We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) program for standardized incidence ratio (SIR), risk factors, and survival of subsequent ANLL, focusing on the period between 2000 and 2014. RESULTS: There was an increased SIR among breast cancer patients for subsequent ANLL (SIR: 2.41; 95% CI: 2.26-2.58). Risk factors of subsequent ANLL were age at first cancer diagnosis (40+ vs. 15-39 years, aHR =1.572, P=0.003), tumor size (21-50 vs. ≤20 mm, aHR =1.332, P=0.003; 50+ vs. ≤20 mm, aHR =1.735, P<0.001), chemotherapy exposure (yes vs. no, aHR =1.692, P<0.001), and radiation exposure (yes vs. no, aHR =1.232, P=0.002). Meanwhile, following subsequent ANLL, survivors had an adverse overall survival (OS) compared with patients who did not develop ANLL (aHR =3.359, P<0.001). CONCLUSIONS: Breast cancer survivors have a higher risk of developing subsequent ANLL compared to the general population. Increased vigilance should be shown towards the potential development of ANLL due to older age, larger tumor size, chemotherapy, and radiation exposure in survivors.