bims-merabr 2026-09-13 papers

Science. 2026 Sep 10. 393(6816): eaea4287

Lean adipocyte oxylipin signaling restrains breast cancer through ferroptosis.

Meghan C Curtin, Abigail E Jackson, Mark D Lee, Elisabeth A Brown, J Alan Maschek, David H Lum, James E Cox, Alana L Welm, Keren I Hilgendorf.

Obesity increases breast cancer risk and tumor aggressiveness, yet the mechanisms underlying this association remain unclear. In this work, we identify a tumor-suppressive lipid signaling pathway in which mammary adipocytes secrete the oxylipin 9S-hydroxyoctadecadienoic acid (9S-HODE). 9S-HODE induces ferroptosis in breast cancer cells by disrupting iron homeostasis. Adipocytes in obese mammary tissue produce less 9S-HODE, and tumors in obese mice exhibit reduced ferroptosis. Accordingly, ferroptosis inhibition accelerates tumor growth in lean mice, and restoring 9S-HODE suppresses tumor growth in obese mice. In humans, mammary 9S-HODE content is inversely correlated with body mass index, and 9S-HODE inhibits patient-derived breast cancer organoid growth. These findings identify the loss of adipocyte-derived 9S-HODE as a mechanism by which obesity promotes breast cancer and suggest that the restoration of ferroptosis-inducing lipid signaling may be a therapeutic strategy.

DOI: https://doi.org/10.1126/science.aea4287

JCI Insight. 2026 Sep 08. pii: e197357. [Epub ahead of print]11(17):

Estrogen promotes tumor phenotypes in ER+ and ER- breast cancer through UGDH-GPR30.

Meghan J Price, Annee D Nguyen, Corinne H Strawser, Trupti Trivedi, Cesar Cd Baeta, Catherine Lavau, Jovita K Byemerwa, Debarati Mukherjee, Suzanne E Wardell, Sandeep Artham, Vardhman Kumar, Shyni Varghese, C Rory Goodwin.

Estrogen can promote aggressive tumor phenotypes in estrogen receptor-positive (ER+) breast cancer; however, ER- cell lines are not widely considered estrogen responsive. Noncanonical estrogen-stimulated pathways such as the membrane-bound G protein-coupled estrogen receptor (GPR30) can mediate migratory and proliferative phenotypes in breast cancer and are postulated to promote resistance to aromatase therapies. Moreover, dysregulation of UDP-glucose 6-dehydrogenase (UGDH), a ubiquitously expressed enzyme critical to the metabolism of UDP-glucuronic acid into extracellular matrix precursors and hormone regulation, is associated with tumorigenesis. Here, we illustrated the impact of estrogen stimulation on tumor phenotypes in ER+ and ER- cell models in vitro and in vivo. We then demonstrated UGDH's association with metastatic breast cancer via single-cell sequencing of patient specimens. Genetic knockdown of UGDH blunted estrogen-stimulated tumor phenotypes in vitro, ex vivo, and in vivo using both ER+ and ER- breast cancer lines. Finally, we demonstrated that UGDH knockdown blunted noncanonical estrogen stimulation through GPR30. Ultimately, our study validated prior studies demonstrating estrogen-responsive malignant phenotypes in ER- breast cancer and demonstrated that estrogen-stimulated breast cancer progression can be mediated through noncanonical pathways (e.g., UGDH/GPR30), regardless of ER status.

Keywords: Breast cancer; Endocrinology; G protein-coupled receptors; Oncogenes; Oncology

DOI: https://doi.org/10.1172/jci.insight.197357

J Pathol Transl Med. 2026 Sep 09.

Obesity-driven adipokine signaling in breast cancer: mechanistic insights, therapeutic challenges, and opportunities for precision oncology.

Vadakke Kunnumma Soonu, Praveen Kumar Shenoy, Valiyaparampil Gopi Deepak Roshan, Vipin Gopinath, Krishnan Sreejith.

Breast cancer is the leading cause of illness and death among women worldwide, with more than 2.3 million new cases diagnosed each year. The incidence and fatality rates are steadily increasing, notably in Asian countries. Obesity has been established as a major and growing risk factor for breast cancer progression. The World Health Organization reports that adult obesity rates have doubled since 1990. Obesity promotes tumor growth by inhibiting adipokine production and activating cancer-promoting pathways. In obese people, the microenvironment surrounding breast cancer cells is drastically altered. This is mostly due to the malfunctioning of adipocytes (fat cells) and macrophages. These defective cells' adipokines alter signaling pathways required for cancer cell proliferation, survival, and inflammation. This dysregulation has a significant role in tumor development, metastasis, and resistance to traditional cancer treatments, particularly in obese patients. This review highlights the role of adipokines in breast cancer, with a focus on disease progression, therapeutic challenges, and knowledge gaps. Clarifying how obesity alters tumor biology is key to advancing personalized and effective treatments for obese patients.

Keywords: Adipokines; Breast neoplasms; Obesity

DOI: https://doi.org/10.4132/jptm.2026.06.30

J Pathol. 2026 Sep 09.

Differential FGFR1 copy number status displays unique tumour immune microenvironment in triple-negative breast cancer.

Yike Gao, Fei Yao, Junyi Pang, Tianlin Sun, Changbin Zhu, Shafei Wu, Zhiyong Liang.

Fibroblast growth factor receptor 1 (FGFR1) amplification, a significant cancer alteration with both prognostic and therapeutic relevance, lacks a standardized definition. The relationship between FGFR1 copy number (CN) variations and tumour microenvironment (TME) characteristics also remains poorly understood. This study defined FGFR1 amplification and investigated TME features across FGFR1 CN subtypes in triple-negative breast cancer (TNBC) to guide precise treatment. We analysed 182 TNBC tumour specimens. FGFR1 CN status was assessed using fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) was performed on 88 samples to explore biological differences. Immunohistochemical (IHC) results for CD3, CD4, and CD8 along with clinical data were analysed. Samples were categorized into four groups based on the FGFR1/CEN8 ratio and the mean FGFR1 signals per cell. Groups 1 (ratio ≥ 2.0, signals ≥ 4.0) and 2 (ratio ≥ 2.0, signals < 4.0) exhibited robust tumour proliferation, increased FGFR signalling, and an immunosuppressive TME. Conversely, group 4 (ratio < 2.0, signals < 4.0) showed significantly enhanced immune cell infiltration (e.g. CD8+ T cells, NK cells), supported by elevated CD3+/CD8+ T-cell densities. Group 3 (ratio < 2.0, signals ≥ 4.0) was heterogeneous: tumours with FGFR1 CN ≥ 5 resembled groups 1/2, while those with CN < 5 mirrored group 4. Thus, FGFR1 amplification (FGFR1-Amp) was defined as FGFR1/CEN8 ratio ≥ 2.0 or CN ≥ 5.0 (14.29% prevalence, 26/182). Remaining cases were FGFR1-neutral (FGFR1-Neu). Immune profiling revealed that FGFR1-Amp & HER2-low TNBC had reduced immune cell infiltration but heightened oncogenic signalling (including epithelial-mesenchymal transition, angiogenesis) compared with other subgroups. In contrast, FGFR1-Neu tumours, especially HER2-zero, displayed increased immune cell infiltration (NK cells, effector cells), MHC I/II molecules, activation markers, and elevated immune checkpoint expression (e.g. PD-L1, CTLA4, LAG3). This study defines FGFR1 amplification in TNBC and characterizes its TME. FGFR1-Amp in HER2-low TNBC correlates with an immunosuppressive environment, potentially hindering HER2-ADC efficacy and suggesting combined FGFR inhibition. Conversely, FGFR1-Neu & HER2-zero tumours with immune activation may respond better to immunotherapy. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: HER2; amplification; fibroblast growth factor receptor 1 (FGFR1); immune cell; triple‐negative breast cancer (TNBC); tumour microenvironment

DOI: https://doi.org/10.1002/path.70121

Genes Dev. 2026 Sep 09.

Dangerous liaisons: interactions between cancer cells and adipocytes as drivers of cancer progression.

Carolina Dehesa Caballero, Almut Schulze.

Metabolic plasticity and flexibility are key characteristics that allow cancer cells to adapt and thrive in different environments. Specifically, cancer cells can dynamically change the routing of metabolic pathways in response to environmental changes and adapt their metabolic activity depending on local nutrient availability. The tumor microenvironment (TME) plays crucial roles in cancer development and progression. It is now widely accepted that different stromal cells, as well as soluble factors, including metabolites, derived from the TME support cancer cell proliferation and survival and drive migration, invasion, and the formation of metastases. Some cancer types grow in the proximity of adipose tissue (AT), which is mostly composed of mature adipocytes, a specialized cell type responsible for the storage and controlled release of lipids. In response to specific stimuli released by cancer cells, adipocytes can transform into cancer-associated adipocytes (CAAs). CAAs release signaling molecules, and provide fatty acids to cancer cells and other cell types in the TME, which can then utilize these fatty acids as fuel. The interaction between cancer cells and adipocytes creates a dynamic cross-talk that promotes disease progression through multiple mechanisms. In this review, we aim to provide an overview of the main factors in the CAA-cancer cell cross-talk, with a focus on the metabolic consequences of this interaction.

Keywords: EMT; cancer-associated adipocytes; fatty acid transport; lipid droplets; metabolic flexibility and plasticity; metastasis; oxidative stress

DOI: https://doi.org/10.1101/gad.353813.126

Front Oncol. 2026 ;16 1853883

The double-edged sword of SASP in breast cancer: from tumor suppression to progression and therapy resistance.

Xianneng Gao, Yunlong Zhang, Yue Sun, Tiefeng Xu.

The senescence-associated secretory phenotype (SASP) represents a complex and dynamic collection of bioactive factors secreted by senescent cells, which exerts dual regulatory effects on breast cancer (BC) progression. When SASP is transiently expressed, it promotes tumor suppression by recruiting immune cells to enhance immunosurveillance against senescent cells, and by transmitting paracrine signals that inhibit cancer cell proliferation. In contrast, when senescent cells cannot be cleared in a timely manner and SASP transitions to a chronic, persistent state, it drives tumor progression through multiple mechanisms, including the promotion of chronic inflammation, induction of epithelial-to-mesenchymal transition (EMT), and facilitation of immune evasion. Unlike previous pan-cancer reviews that largely rely on descriptive literature summaries, this review focuses specifically on BC and integrates pathogenic mechanism analysis with inter-subtype comparisons across BC subtypes. The dual roles of SASP in BC are systematically examined along three dimensions: cellular origin, temporal dynamics, and SASP component heterogeneity. Furthermore, existing SASP-targeted therapeutic strategies are discussed, with the aim of providing novel insights into the potential role of SASP in BC treatment.

Keywords: BC; SASP; The double-edged sword; mechanisms; therapy

DOI: https://doi.org/10.3389/fonc.2026.1853883