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Breast Cancer Scientific Focus Group
Tumor Cell Plasticity and Metastasis
Virtually all breast cancer associated deaths occur due to metastasis. During this multi-step process, the surviving cancer cells must rapidly adapt to many stressors, including hypoxia, lack of cell-cell/matrix interactions, inflammation, immune surveillance, and chemotherapy. Many studies have shown that genetic alterations do not play a dominant role in metastasis. Instead, epigenetic/transcriptional changes have emerged as key means by which tumor cells rapidly respond to stressors during the metastatic cascade. Recently, several groups (including the University of Colorado Anschutz Cancer Center) have shown that in addition to transcription, stress-induced mRNA translation may play a much larger role in tumor cell adaptation than was previously appreciated.
With this scientific focus group, our goal is to test the overarching hypothesis that translational changes in response to microenvironmental stressors drives cancer cell adaptation and survival, resulting in metastasis. Identifying both unique and shared mechanisms of tumor cell adaptation in response to different stressors may enable us to uncover specific means to target breast cancer metastasis. To address this hypothesis, we are working on four different projects:
Project 1
To determine whether translational regulation by eIF3d and eIF3e mediates the hypoxic response, breast cancer cell adaptability and metastasis.
Project 2
To understand how translation regulates adaptation to radiotherapy-induced stress to promote radioresistance in brain metastasis.
Project 3
To determine how pulmonary viral infections alter translational regulation in the lung to promote metastatic outgrowth.
Project 4
To determine how translation in response to chemotherapy induced ER stress contributes to tumor progression and metastasis.
These four projects will be supported by the Multi-Omics Data Integration and Modeling Core. The core will support experimental design for -omic data generation, develop robust and reproducible analysis pipelines, develop methods to integrate multi-omics datasets, and generate novel molecular signatures to evaluate translational changes across projects.
Postpartum Breast Cancer
Research at the University of Colorado Anschutz Cancer Center focuses on understanding how breast cancer cells survive, adapt, and metastasize, with particular attention to postpartum breast cancer, an aggressive subtype diagnosed after childbirth. During the postpartum period, the mammary gland undergoes involution, a normal remodeling process that generates a wound like, inflammatory microenvironment. Studies have shown that breast tumor cells can exploit this temporary physiological state, leveraging involution associated cues to enhance survival, invasion, and resistance to therapy. These findings are especially important given the significantly increased risk of metastasis and poorer clinical outcomes observed in postpartum breast cancer.
Key Research Focus: Semaphorin 7A (SEMA7A)
A central area of investigation is the role of Semaphorin 7A (SEMA7A) as a major regulator of tumor cell adaptation during postpartum involution. Research has demonstrated that SEMA7A functions as a broad mediator of breast cancer progression, supporting tumor cells through multiple mechanisms, including:
- Resistance to cell death.
- Activation of pro survival and cellular stress response pathways, including autophagy.
- Recruitment and activation of macrophages.
- Promotion of lymphangiogenesis.
- Enhancement of immunosuppression.
- Suppression of tumor inhibitory programs.
These mechanisms enable cancer cells to survive in hostile environments-such as the bloodstream or distant tissues-ultimately facilitating metastatic spread. SEMA7A has also been identified as both a biomarker of recurrence and a promising therapeutic target in postpartum breast cancer and in all breast cancers where it is expressed.
In partnership with Pearl Scientific, Inc., a novel antagonistic SEMA7A antibody has been developed and is currently undergoing humanization with the goal of enabling future clinical trials in ER+ and ER- breast cancers.
Approach
This research program integrates molecular, cellular, and in vivo experimental systems to define how cancer cells co-opt normal physiological processes-particularly those associated with postpartum mammary gland involution-to promote disease progression. By uncovering the adaptive pathways that allow tumor cells to survive and metastasize, the work aims to identify critical vulnerabilities that can be leveraged to develop new therapeutic strategies. This approach ultimately supports the broader goal of improving outcomes for individuals with postpartum breast cancer as well as those with breast cancers that express SEMA7A.
Project Leads
Heide Ford, PhD
Tumor Cell Plasticity and Metastasis
Virginia Borges, MD
Postpartum Breast Cancer