Biology subjects

Wik, E.

Publications and source records attributed to Wik, E..

4 recordsLinked to original sources

bioRxiv2026

ERα-regulated IRX3 controls the growth of ER-positive breast tumors

Estrogen receptor positive (ER+) breast cancer is primarily treated with endocrine therapies targeting ER signaling. Although endocrine therapy has substantially improved survival in ER+ breast cancer, metastatic disease remains largely incurable, underscoring the need to elucidate additional mechanisms driving growth and proliferation. Here, we show that the homeobox protein IRX3 is selectively overexpressed in ER+ breast cancer and define the molecular function of IRX3 in ER+ breast cancer using an integrated combination of in vitro, in vivo and in silico approaches. We uncover a previously uncharacterized distal regulatory region that controls IRX3 transcription via ER and associated steroid receptor coactivators. Consistent with this regulatory axis, anti-estrogen treatment resulted in marked downregulation of cellular IRX3 levels. Functionally, depletion of IRX3 suppresses proliferation of the human ER+ breast cancer cells in vitro, but paradoxically promotes tumor growth and metastatic dissemination in orthotopic xenografts in vivo by stimulating enhanced tumor vascularization. Finally, low tumor expression of IRX3 correlates with poorer survival outcomes in patients with ER+ breast cancer. Collectively, these findings establish IRX3 as an important regulator of ER+ breast tumor biology and reveal an ER-dependent role for IRX3 in modulating proliferative and vascular programs in tumor progression. SignificanceBy identifying a novel ER-dependent regulatory pathway, this work refines our understanding of how hormone signaling shapes both breast tumor growth and the surrounding microenvironment.

cancer biology↗

bioRxiv2025

Podoplanin-Linked Mesenchymal Shift Synergizes with CCR7 driving Lymphatic Metastasis and Tumor Progression in Breast Cancer

Epithelial-to-mesenchymal-transition (EMT) and upregulation of chemokine receptors are linked to lymphatic metastasis in various types of cancer including breast cancer. However, the underlying molecular mechanisms are not fully understood. Using a triple-negative mammary carcinoma model, conditioned for lymphatic metastasis through expression of the C-C chemokine receptor 7 (CCR7), we identified intrinsic tumor plasticity associated with EMT as a critical determinant for effective metastasis. Specifically, tumor cells upregulate Podoplanin (PDPN) as part of a spontaneous mesenchymal shift that promotes lymphatic dissemination and tumor growth. Intriguingly, the expression of CCR7, or PDPN alone, was not sufficient for these effects. CCR7- and PDPN-positive tumors displayed an immune-cold tumor profile, compared to control, characterized by reduced tumor-infiltrating T-cells. Consistent with this, we found that spontaneous upregulation of PDPN was linked to hypoxia and was associated with the downregulation of homeostatic interferon signaling, and increased expression of collagens. Analysis of single-cell data sets showed that PDPN expression was heterogeneous and correlated significantly with EMT markers, collagen expression, and hypoxia hallmark in human breast cancer cell lines and primary human triple negative (TN) breast cancer, mirroring findings in the mouse model. Further analysis of the human breast cancer METABRIC-microarray datasets supported an association between a high CCR7/PDPN mRNA expression score and aggressive breast cancer subtypes with an independent prognostic value in lymph node-positive tumors. Together, these findings highlight a critical role of tumor microenvironment-driven tumor plasticity and molecular synergy between CCR7 and PDPN-coupled EMT shift in promoting chemokine receptor-mediated tumor dissemination and progression. SummaryCCR7-driven lymphatic metastasis requires a mesenchymal shift with PDPN upregulation. This tumor plasticity, linked to hypoxia and immune evasion, suggests CCR7-PDPN synergy in aggressive breast cancer progression and poor prognosis.

cancer biology↗

bioRxiv2023

Age-related phenotypes in breast cancer: a population- based study

Breast cancer in young (<40 years) is associated with a higher frequency of aggressive tumor types and poor prognosis. It remains unclear if there is an underlying age-related biology that contributes to the unfavorable outcome. We aim to investigate the relationship between age and breast cancer biology, with emphasis on proliferation. Clinico-pathologic information, immunohistochemical markers, and follow-up data were obtained for all patients aged <50 (Bergen cohort-1; n=355) and compared to previously obtained information on patients aged 50-69 (Bergen cohort-2; n=540), who participated in the Norwegian Breast Cancer Screening Program. Data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) was applied for validation and for analyses of gene expression signatures. Young breast cancer patients presented more aggressive tumor features such as hormone receptor negativity, HER2 positivity, lymph-node metastasis, the HER2-enriched and triple negative subtypes, and shorter survival. Age <40 was significantly associated with features of stemness and higher proliferation (by Ki67), also in molecular subsets. Ki67 showed weaker prognostic value in young patients. We point to aggressive phenotypes, increased tumor cell proliferation and stem-like features in breast cancer of the young. Hence, tumors of young breast cancer patients may have a unique biology, also when accounting for screen/interval differences, that may open for new clinical opportunities, stratifying treatment by age.

pathology↗

bioRxiv2022

Neurogenesis and angiogenesis are associated features of aggressive breast cancer

The tumor microenvironment (TME) is important for cancer growth and progression. While angiogenesis is an established hallmark of cancer, the role of nerve fibers is less studied. Here, we investigated neurogenesis and angiogenesis in breast cancer and found them to be closely associated. Single-cell based spatial mapping by imaging mass cytometry (IMC) indicated close proximity between neural and vascular structures. Subsequent validation by tissue-based markers of neurogenesis and angiogenesis, supported by proteomics and transcriptomics data of tissues and cell lines, supported a link between these processes. A consolidated neuro-angiogenic signature score was linked to high-grade breast cancer and reduced patient survival, also within the low-grade luminal tumor subgroup. Our findings support that neurogenesis and angiogenesis are related in aggressive breast cancer and might possibly improve tumor stratification and clinical management.

cancer biology↗