Distinct invasive patterns in situ between estrogen receptor-positive and triple-negative breast cancer through the intraductal tracking of carbon nanoparticles.

Given that the transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (BC) is crucial during the BC progression, the mechanism involved in the invasion transition behind triple-negative breast cancer (TNBC) and estrogen receptor-positive (ER-positive) subtype has remained elusive. This article detected distinct invasion patterns of BC cells between the ER-positive and TNBC using intraductal murine models with intraductal administration of carbon nanoparticles (CNPs). First, the feasibility of the utility of CNPs as a tracer was proved. The area ratio of CNPs and tumor cells invading the stroma at the late stage was found significantly higher than that in the early stage in MNU-induced ER-positive BC. However, opposite results were obtained in the triple-negative model. Consequently, we proposed that the ER-positive phenotype cells behave differently between different stages during tumor progression while there is no such difference in the invasion process of TNBC cells. The analysis regarding the duct integrity along with immunohistochemical characteristics further explained the distinct invasion features between the ER-positive and triple-negative subtypes. Last, the relationship between the duct thickness and the duct integrity suggested that ER-positive tumors gradually increased in size within the lumen before the invasion. Overall, this study suggested the different invasion characteristics of ER-positive BC and TNBC in vivo.

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 Therapy in Breast Cancer: Current Status and Future Prospective.

With our improved understanding of the biological behavior of breast cancer, minimally invasive intervention is urgently needed for personalized treatment of early disease. Intraductal therapy is one such minimally invasive approach. With the help of appropriate tools, technologies using the intraductal means of entering the ducts may be used both to diagnose and treat lesions in the mammary duct system with less trauma and at the same time avoid systemic toxicity. Traditional agents such as those targeting pathways, endocrine therapy, immunotherapy, or gene therapy can be used alone or combined with other new technologies, such as nanomaterials, through the intraductal route. Additionally, relevant mammary tumor models in rodents which reflect changes in the tumor microenvironment will help deepen our understanding of their biological behavior and heterogeneity. This article reviews the current status and future prospects of intraductal therapy in breast cancer, with emphasis on ductal carcinoma in situ.

Deciphering the single-cell transcriptome network in keloids with intra-lesional injection of triamcinolone acetonide combined with 5-fluorouracil.

Objectives: Keloid is a highly aggressive fibrotic disease resulting from excessive extracellular matrix deposition after dermal injury. Intra-lesional injection of triamcinolone acetonide (TAC) in combination with 5-fluorouracil (5-FU) is a commonly used pharmacological regimen and long-term repeated injections can achieve sustained inhibition of keloid proliferation. However, the molecular mechanisms underlying the inhibitory effect on keloids remain insufficiently investigated. Methods and materials: This study performed single-cell RNA sequencing analysis of keloids treated with TAC+5-FU injections, keloids, and skins to explore patterns of gene expression regulation and cellular reprogramming. Results: The results revealed that TAC+5-FU interrupted the differentiation trajectory of fibroblasts toward pro-fibrotic subtypes and induced keloid atrophy possibly by inhibiting the FGF signaling pathway in intercellular communication. It also stimulated partial fibroblasts to develop the potential for self-replication and multidirectional differentiation, which may be a possible cellular source of keloid recurrence. T cell dynamics demonstrated elevated expression of secretory globulin family members, which may be possible immunotherapeutic targets. Schwann cell populations achieved functional changes by increasing the proportion of apoptotic or senescence-associated cell populations and reducing cell clusters that promote epidermal development and fibroblast proliferation. Conclusions: Our findings elucidated the molecular and cellular reprogramming of keloids by intra-lesional injection of TAC+5-FU, which will provide new insights to understand the mechanism of action and therapeutic targets.

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.

Comparison of the ductal carcinoma in situ between White Americans and Chinese Americans.

ABSTRACT: Currently, the wide-spread use of screening mammography has led to dramatic increases in ductal carcinoma in situ (DCIS). However, DCIS of Chinese Americans, the largest Asian subgroup in American, has rarely been comprehensively studied over the past decade. This work compared the DCIS characteristics and prognosis of Chinese American patients with White Americans in the USA to determine the characteristics and prognosis of DCIS patients of Chinese Americans.The data were obtained using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. The diagnosis and treatment variables between the two groups were compared by means of Chi-square tests. Survival was determined with the use of the Kaplan-Meier method and the multivariable Cox proportional hazard regression model.From 1975 to 2016, 81,745 White Americans and 2069 Chinese Americans were diagnosed with ductal carcinoma in situ. Compared with the white patients, the Chinese Americans were younger (P < .001) with smaller tumors (P < .001) and higher family income (P < .001). DCIS patients of Chinese American group accounted for a higher percentage of all breast cancers than the whites (P < .001). In the multivariable Cox proportional hazard regression analysis, Chinese American was an independent favorable prognostic factor in terms of overall survival (OS) (HR, 0.684; 95% CI, 0.593-0.789; P < .001) compared with the white group.In conclusion, DCIS characteristics of the Chinese group, which exhibited a higher proportion of younger age, a higher DCIS ratio, and a better prognosis, were distinct from those of the White Americans.

Breast surgery for young women with early-stage breast cancer: Mastectomy or breast-conserving therapy?

ABSTRACT: Whether breast-conserving therapy (BCT) should be chosen as a local treatment for young women with early-stage breast cancer is controversial. This study compared the survival benefits of BCT or mastectomy in young women under 40 with early-stage breast cancer and further explored age-stratified outcomes. This study investigated whether there is a survival benefit when young women undergo BCT compared with mastectomy.The characteristics and prognosis of white women under 40 with stage I-II breast cancer from 1988 to 2016 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. These women were either treated with BCT or mastectomy. The log-rank test of the Kaplan-Meier survival curve and Cox proportional risk regression model were used to analyze the data and survival. The analysis was stratified by age (18-35 and 36-40 years).A total of 23,810 breast cancer patients were included, of whom 44.9% received BCT and 55.1% underwent mastectomy, with a median follow-up of 116 months. Patients undergoing mastectomy had a higher tumor burden and younger age. By the end of the 20th century, the proportion of BCT had grown from nearly 35% to approximately 60%, and then gradually fell to 35% into the 21st century. Compared with the mastectomy group, the BCT group had improved breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.917; 95% CI, 0.846-0.995, P = .037) and overall survival (OS) (HR 0.925; 95% CI, 0.859-0.997, P = .041). In stratified analysis according to the different ages, the survival benefit of BCT was more pronounced in the slightly older (36-40 years) group while there was no significant survival difference in the younger group (18-35 years).In young women with early-stage breast cancer, BCT showed survival benefits that were at least no worse than mastectomy, and these benefits were even better in the 36 to 40 years age group. Young age may not be a contraindication for BCT.

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.