bims-merabr 2025-10-05 papers

Cancer Invest. 2025 Sep 29. 1-14

Interplay Between ERK1/2 Signaling Pathway and Estradiol Receptor Modulates ER Targeted Genes Involved in Progression of Estrogen Responsive Breast Cancers.

Rajeshwari H Patil, Kavya K, Naveen Kumar M, Paturu Kondaiah.

Breast cancer is a leading global health concern, while the endocrine resistance in breast cancer poses a critical challenge, directly undermining the long-term effectiveness of hormone therapies and significantly impacting patient survival and treatment outcomes. Hence, the present study aims to elucidate the non-genomic mechanism of ERK1/2 signalling pathway, in conjunction with ER and GPR30 receptors involved in regulation of breast cancer progression in MCF-7 and T47D cells. We assessed cell proliferation using MTT and Trypan blue assays, expression studies by reverse transcription quantitative PCR and western blot analysis, the migratory abilities of cells by scratch-wound healing assay. Our results revealed significant down (90%) regulation of E2-induced ERK phosphorylation, inturn suppression of proliferation rate by 30% and migration by 35% using small molecular inhibitors of ERK in MCF-7 and T47D cells confirming ERK as the central direct target for breast cancer proliferation and development. Collectively, our results suggest that E2-induced 1.5-fold upregulation of phospho ERK1/2 expression promotes breast cancer cell proliferation and migration via a Src/EGFR/ERK pathway. These findings provide a novel strategy of combining endocrine therapy with targeted agents (ERK inhibitors), a cornerstone in managing endocrine-resistant condition, delaying progression and improving outcomes in the treatment of breast cancer.

Keywords: Cell migration assay; ERK inhibitors; ERK1/2; Estradiol receptor; GPR30; Western blot

DOI: https://doi.org/10.1080/07357907.2025.2563715

Front Oncol. 2025 ;15 1655438

FGFR2 expression relates to subtype-specific tumour microenvironment (TIME) during luminal breast cancer evolution.

Julia Sołek, Aleksandra Zielińska, Radzisław Kordek, Hanna Romańska, Marcin Braun.

Background: Fibroblast growth factor receptor 2 (FGFR2) is an oncogenic driver in luminal breast cancer (BCa), with emerging evidence linking it to tumour immune microenvironment (TIME) modulation. While FGFR2's role in endocrine resistance is established, its potential involvement in shaping immune infiltration-particularly in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC)-remains underexplored.
Methods: This retrospective study analysed 99 BCa specimens collected between 2004-2019. Immunohistochemistry was used to assess FGFR2 expression and immune markers (CD8, CD68, CD163, FOXP3). Clinical and pathological variables were evaluated, and immune cell densities were compared across disease stages and BCa subtypes (luminal vs. non-luminal). Correlations between FGFR2 expression and immune markers were assessed using non-parametric statistical tests.
Results: Progression from DCIS to IDC was associated with increased infiltration by CD8+ T cells and CD68+ macrophages. FGFR2 expression showed differences between DCIS and IDC with an extensive DCIS component and was positively correlated with CD8+, CD163+, and FOXP3+ cell densities. The latter associations were exclusive to luminal A tumours, with no such correlations observed in non-luminal subtypes.
Conclusions: FGFR2 expression in luminal A BCa correlates with markers of immunosuppressive TIME, particularly CD163+ macrophages and FOXP3+ T cells. These subtype-specific interactions suggest a synergistic role of FGFR2 and estrogen receptor signalling in immune evasion and tumour progression, warranting further mechanistic and therapeutic investigation. However, the small number of cases in certain subgroups, particularly DCIS and non-luminal tumours, limits the generalizability of these findings and warrants cautious interpretation.

Keywords: FGFR2; breast cancer; ductal carcinoma in situ; fibroblast growth factor receptors; invasive breast cancer; tumour immunemicroenvironment; tumour-associated macrophages; tumour-infiltrating lymphocytes

DOI: https://doi.org/10.3389/fonc.2025.1655438

Cell Biol Int. 2025 Sep 29.

Matter of Fat: Cancer-Associated Adipocytes as Mediators of Tumor Progression and Immune Evasion.

Niti Sureka, Shikhar Chohan, Samreen Zaheer, Durre Aden, Sana Ahuja, Amit H Agravat, Seema Goel, Jaseem Hassan, Laltlanzovi Chawgthu, Hage Nobin, Sufian Zaheer.

Peritumoral adipocytes that exhibit changes in their phenotype and distinct biological characteristics, such as reduced expression of mature adipocyte differentiation markers, increased secretion of adipocyte-derived factors, and facilitation of metabolic reprogramming in cancer cells, are referred to as cancer-associated adipocytes (CAAs). CAAs are increasingly recognized as important contributors to tumor initiation, progression, and metastasis within the tumor microenvironment (TME). Found predominantly in fat-rich tissues such as breast, ovarian, colorectal, and pancreatic cancers, CAAs undergo significant functional changes when exposed to cancer cells. These changes include lipid transfer to cancer cells, secretion of pro-inflammatory cytokines, and remodeling of the extracellular matrix, all of which enhance cancer cell survival, proliferation, and invasion. The TME, composed of various non-cancerous cells, extracellular matrix components, and signaling molecules, plays a dynamic role in influencing tumor behavior and treatment response. CAAs engage in a reciprocal interaction with cancer cells, transforming from normal adipocytes to tumor-promoting cells while simultaneously driving cancer aggressiveness. Understanding the mechanisms through which CAAs contribute to cancer progression offers promising avenues for novel therapeutic strategies targeting the TME to combat cancer more effectively.

Keywords: cancer associated adiopocytes; pre‐adipocyrtes; tumor microenvironment

DOI: https://doi.org/10.1002/cbin.70085

bioRxiv. 2025 Sep 27. pii: 2025.09.25.678463. [Epub ahead of print]

Joint Mapping of Chromatin Accessibility and Targeted Proteomics in HER2-expressing Breast Cancer Systems.

Anna Fomitcheva Khartchenko, Trinh Lam, Nadine Goldhammer, Marin Bont, Shruti Warhadpande, Jennifer M Rosenbluth, Amy E Herr.

HER2 proteoforms promote therapeutic resistance and aggressiveness in HER2-positive breast cancer, yet their epigenetic consequences remain poorly defined. Here, we establish EpiBlot, a joint assay incorporating a customized plateATAC-seq workflow that minimizes sample inputs with single-cell western blotting to concurrently profile chromatin accessibility with protein and proteoform expression in breast cancer MCF7 cells. Engineered MCF7 cells expressing HER2 proteoforms - full-length p185HER2 or truncated 611-CTF - were evaluated on the impact of such proteoforms after lapatinib or doxorubicin exposure. Expression of 611-CTF elicits pervasive chromatin remodeling, whereas p185HER2 provokes only modest accessibility shifts under the same treatments. Lapatinib treatment produces limited global effects but unmasks proteoform-specific responses, while treatment with doxorubicin drives extensive genome-wide accessibility changes. Concordance between chromatin accessibility and protein abundance is moderate, underscoring complex regulatory coupling. Extending this dual-modality approach to HER2-low patient-derived organoids uncovers distinct chromatin states and reveals a subpopulation of triple-negative breast-cancer cells expressing truncated HER2 proteoforms. These findings highlight the value of multimodal profiling with proteoform identification for dissecting tumor heterogeneity and therapeutic response in HER2-positive breast cancer.
Graphical abstract:
Highlights: To evaluate the impact of chromatin accessibility on HER2 proteoform expression, we introduce EpiBlot, a novel workflow combining a plateATAC-seq assay (i.e., mini-96 well-plate requiring 5-500 nuclei) with single-cell Western blot.Increased chromatin accessibility and significantly larger nuclei were detected in a breast cancer cell line (MCF7) engineered to express the truncated HER2 proteoform (611-CTF) versus a line expressing only the full-length HER2 protein.Lapatinib-targeted treatment did not induce widespread changes in chromatin accessibility.Doxorubicin reshapes chromatin accessibility in HER2-proteoform cell lines, producing both gains and losses across the genome.Chromatin accessibility and protein abundance are moderately correlated, with a wide range of protein abundance measured across single cells.HER2-low patient-derived breast cancer organoids exhibit decreased accessibility in the ERBB2 region despite increased HER2 protein expression, as compared to normal breast cells.

DOI: https://doi.org/10.1101/2025.09.25.678463

Cell Div. 2025 Oct 02. 20(1): 22

FGF4 drives tumor progression in triple-negative breast cancer via IL6/STAT3-mediated macrophage M2 polarization and immune suppression.

Xuanhe Zhang, Shushan Zhang, Yuanyuan Han.

OBJECTIVE: This study investigates how Fibroblast Growth Factor 4 (FGF4) drives triple-negative breast cancer (TNBC) progression by modulating macrophage polarization through the IL6/STAT3 signaling axis, with a focus on immune suppression and tumor microenvironment remodeling.
METHODS: TNBC transcriptomic datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify FGF4-associated pathways using differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and immune infiltration profiling via Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT). Functional annotations (GO/KEGG) highlighted IL6/STAT3 as a key pathway. In vitro models with FGF4-overexpressing or knockdown TNBC cells were co-cultured with macrophages to assess IL6/STAT3 activation, M2 polarization markers (CD206, Arg1), and cytokine secretion (ELISA). Tumor cell behaviors (proliferation, migration, invasion) were quantified. In vivo orthotopic TNBC models in mice evaluated FGF4's impact on tumor growth, immune cell infiltration (flow cytometry), and STAT3 activity (Western blot).
RESULTS: FGF4 was upregulated in TNBC and strongly correlated with M2 macrophage infiltration. In vitro, FGF4 activated IL6/STAT3 signaling, inducing macrophage polarization to an M2 phenotype with elevated IL-10/TGF-βsecretion and suppression of T cell proliferation. Conditioned media from M2 macrophages enhanced TNBC cell aggressiveness. In vivo, FGF4-overexpressing tumors showed higher weight and increased M2 markers, whereas FGF4 knockdown reduced tumor volume and enhanced CD8+ T cell infiltration.
CONCLUSION: FGF4 promotes TNBC progression by activating IL6/STAT3 to reprogram macrophages into immune-suppressive M2 effectors, fostering a tumor-permissive microenvironment. Targeting FGF4 may disrupt this crosstalk, offering a novel immunotherapeutic strategy for TNBC.

Keywords: FGF4; IL6/STAT3 signaling; Immune suppression; Macrophage polarization; Triple-negative breast cancer

DOI: https://doi.org/10.1186/s13008-025-00164-y