Ling-Zhi Xv

Background: Breast invasive lobular carcinoma (ILC) with multiple organ metastases at initial diagnosis is rare. This study reports a case of ILC presenting with bone marrow and bone metastases at first diagnosis, in which the patient developed gastrointestinal metastases (GIMs) one year later, and reviews the relevant literature. Case Description: A 35-year-old female patient presented with a left breast mass accompanied by enlarged left axillary and cervical lymph nodes as well as thoracolumbar pain. Pathological biopsy confirmed the diagnosis of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-low ILC, with metastases to the left axillary and cervical lymph nodes, bone marrow, and bone. The patient achieved tumor remission following treatment with endocrine therapy combined with a CDK4/6 inhibitor. One year later, she developed gastrointestinal symptoms such as nausea and vomiting. Pathological biopsy confirmed GIM from ILC, and the metastatic tumors harbored an ESR1 mutation (ESR1M) at p.Y537N. After treatment with the anti-HER2 antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd), disease control was achieved. Conclusions: Although ER-positive and HER2-low ILC can derive clinical benefit from endocrine therapy combined with a CDK4/6 inhibitor, the tumor may still undergo occult progression, such as ESR1M and GIM. This case highlights the importance of dynamic biomarker monitoring and repeat biopsy when occult progression is suspected. Anti-HER2 ADC therapy may provide disease control and clinical benefit in selected patients with HER2-low ILC after endocrine resistance.

Breast cancer is the most prevalent malignant tumor and a leading cause of cancer-related mortality among women globally. Genetic polymorphisms play critical roles in breast cancer susceptibility, pathogenesis, diagnosis, treatment response, and prognosis. For instance, in terms of pathogenesis, high-penetrance gene mutations (e.g., BRCA1/2, TP53) and low-penetrance gene polymorphisms (identified by genome-wide association studies) significantly increase the risk of breast cancer across diverse ethnic populations and impact key regulatory pathways, including DNA damage repair, inflammation, and cell proliferation/apoptosis. In the field of treatment, breakthroughs have been made in targeted therapies based on genetic polymorphisms. In the realm of prognostic assessment, polygenic risk scores, combined with common genetic variations, are employed to evaluate disease risk, providing a basis for individualized treatment. Additionally, genetic variants (e.g., TOX3/TNRC9 rs3803662) are associated with breast cancer metastasis and poor prognosis, serving as novel prognostic biomarkers. These studies have deepened our understanding of the genetic mechanisms underlying breast cancer and propelled the advancement of precision medicine. Here, we will review the recent research progress in breast cancer from the perspective of genetic polymorphisms.

In recent years, the incidence of breast cancer (BC) and its distant metastases, including ocular metastasis (OM), has continued to rise. However, reports on BC-OM remain scarce. OM is rare and often asymptomatic. It can be easily masked by metastases in other organs, increasing the risk of misdiagnosis, and thus warrants greater clinical attention. In this paper, we describe three cases of BC-OM, review its epidemiological and clinical features, and summarize diagnostic methods and treatment strategies. Our aim is to provide a reference for clinical practice, support standardized management, and ultimately improve patient survival and quality of life (QoL).

Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila (A. muciniphila), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.

The mediator complex usually cooperates with transcription factors to be involved in RNA polymerase II‐mediated gene transcription. As one component of this complex, MED27 has been reported in our previous studies to promote thyroid cancer and melanoma progression. However, the precise function of MED27 in breast cancer development remains poorly understood. Here, we found that MED27 was more highly expressed in breast cancer samples than in normal tissues, especially in triple‐negative breast cancer, and its expression level was elevated with the increase in pathological stage. MED27 knockdown in triple‐negative breast cancer cells inhibited cancer cell metastasis and stemness maintenance, which was accompanied by downregulation of the expression of EMT‐ and stem traits‐associated proteins, and vice versa in non‐triple‐negative breast cancer. Furthermore, MED27 knockdown sensitized breast cancer cells to epirubicin treatment by inducing cellular apoptosis and reducing tumorsphere‐forming ability. Based on RNA‐seq, we identified KLF4 as the possible downstream target of MED27. KLF4 overexpression reversed the MED27 silencing‐mediated arrest of cellular metastasis and stemness maintenance capacity in breast cancer in vitro and in vivo. Mechanistically, MED27 transcriptionally regulated KLF4 by binding to its promoter region at positions −156 to +177. Collectively, our study not only demonstrated the tumor‐promoting role of MED27 in breast cancer progression by transcriptionally targeting KLF4, but also suggested the possibility of developing the MED27/KLF4 signaling axis as a potential therapeutic target in breast cancer.

Objective: Triple-negative breast cancer (TNBC) is distinguished by early recurrence and metastases, a high proclivity for treatment resistance, and a lack of targeted medicines, highlighting the importance of developing innovative therapeutic techniques. Salvia chinensis Benth (SCH) has been widely studied for its anticancer properties in a variety of cancers. However, its significance in TNBC treatment is rarely discussed. Our study investigated the anticancer effect of SCH on TNBC and the underlying mechanisms.Methods: First, we used clonogenic, cell viability, flow cytometry, and Transwell assays to assess the effect of SCH on TNBC. Bioinformatic studies, especially network pharmacology-based analysis and RNA sequencing analysis, were performed to investigate the constituents of SCH and its molecular mechanisms in the suppression of TNBC. High-performance liquid chromatography and thin-layer chromatography were used to identify two major components, quercetin and β-sitosterol. Then, we discovered the synergistic cytotoxicity of quercetin and β-sitosterol and assessed their synergistic prevention of cell migration and invasion. Breast cancer xenografts were also created using MDA-MB-231 cells to test the synergistic therapeutic impact of quercetin and β-sitosterol on TNBC in vivo. The impact on the DNA damage and repair pathways was investigated using the comet assay and Western blot analysis.Results: Our findings showed that SCH decreased TNBC cell growth, migration, and invasion while also inducing cell death. We identified quercetin and β-sitosterol as the core active components of SCH based on a network pharmacology study. According to RNA sequencing research, the p53 signaling pathway is also regarded as a critical biological mechanism of SCH treatment. The comet assay consistently showed that SCH significantly increased DNA damage in TNBC cells. Our in vivo and in vitro data revealed that the combination of quercetin and β-sitosterol induced synergistic cytotoxicity and DNA damage in TNBC cells. In particular, SCH particularly blocked the inter-strand cross-link repair mechanism and the double-strand breach repair caused by the homologous recombination pathway, in addition to inducing DNA damage. Treatment with quercetin and β-sitosterol produced similar outcomes.Conclusion: The current study provides novel insight into the previously unknown therapeutic potential of SCH as a DNA-damaging agent in TNBC.

The treatment options for cancer of unknown primary (CUP) are challenging due to the lack of knowledge about the primary sites, often resulting in a poor prognosis. The emerging next-generation sequencing (NGS) technique has provided a reliable approach to facilitate tumor primary site prediction and targetable gene alteration identification for CUP patients. In this report, we described a 63-year-old female patient who experienced recurrent CUP. NGS-based genetic profiling results revealed a pathogenic germline BRCA1 R71K mutation. Accordingly, the patient received the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib treatment and demonstrated a favorable response to this treatment. Our case suggests that NGS holds great promise for providing improved diagnosis and treatment options to patients with CUP, warranting further clinical investigation.

The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region-proto-oncogene tyrosine-protein kinase (BCR-ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR-ABL1 transcripts vary. Each BCR-ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed-phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph-positive leukemia and highlight key findings regarding leukemogenesis.