Aquaporin 4 over-expression in metastases to the brain in breast cancer.

Breast cancer is a leading killer of women in the United States (1) and the main reason women diagnosed with breast cancer die is metastasis, or spread of the cancer from the breast to a distant organ site (2, 3). We mined public datasets (4, 5) to perform systems-level analyses of the most significant differences in gene expression (6) between breast cancers in humans and the metastases they generate. We found that fibulin-1, fibulin-2 and fibulin-5 were among the genes whose expression was most different between primary tumors of the breast and metastases to both the brain and the soft tissues. Moreover, we found uniform and significantly decreased expression of each differentially expressed fibulin gene in both tissue types. Fibulins-1, -2 and -5 should be targeted to assess whether over-expression of these genes can halt, delay or reverse metastasis in women with breast cancer.

Brain metastases from patients with breast cancer coordinately down-regulate a network of collagen genes.

10.31219/osf.io/5akpw ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Therapeutic Strategy ◽

Treatment Options ◽

Metastatic Breast ◽

Breast Tumors ◽

Metastatic Process ◽

Collagen Genes ◽

Breast cancer is one of the most common cancers in women and a leading cause of death for women (1). Metastasis, the spread of the cancer from the site of the primary tumor to a foreign site, is, in general, the reason why humans die from cancer (2). There are limited treatment options for women with metastatic breast cancer, which can spread from the breast to the brain (3). We compared the transcriptomes of 16 breast tumors to the transcriptomes of 16 brain metastases from the same patients using a published dataset (4). We discovered that 12 independent genes of the collagen family were among the genes whose expression was most different between primary breast tumors in humans and the brain metastases that they generate when considering the entire transcriptome. Each of these collagen genes were expressed at significantly lower levels in metastases to the brain than in tumors of the breast. The biology of collagen genes in the metastatic process in breast cancer should be evaluated as a novel therapeutic strategy in metastatic breast cancer.

BSCI-11. STROMAL PLATELET DERIVED GROWTH FACTOR RECEPTOR-β (PDGFRβ) PROMOTES BREAST CANCER BRAIN METASTASIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.009 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i3-i3

Author(s):

Katie Thies ◽

Anisha Hammer ◽

Blake Hildreth ◽

Luke Russell ◽

Steven Sizemore ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Brain Metastasis ◽

Brain Metastases ◽

Tumor Cells ◽

Mammary Tumor ◽

Growth Factor Receptor ◽

Platelet Derived Growth Factor ◽

Mammary Tumor Cells ◽

Abstract Stromal platelet-derived growth factor receptor-beta (PDGFRβ) has emerged as an actionable mediator of breast tumor-stromal communication. As a receptor tyrosine kinase, PDGFRβ is activated by its ligand, PDGFB, which is released by neighboring tumor epithelium and endothelium. However, how PDGF signaling mediates breast cancer (BC) initiation, progression, and metastasis remains unclear. To evaluate PDGFRβ in this disease, we developed a mouse model of stromal-specific PDGFRβ activation using the Fsp-cre transgene previously published by our group. Mesenchymal-specific activation of PDGFRβ promotes preferential experimental brain metastasis of PDGFB-expressing mammary tumor cells when injected intravenously and accelerates intracranial tumor growth of these cells. Mammary tumor cells expressing low levels of PDGFB do not exhibit a similar increase in brain metastases in PDGFRβ mutant mice. To our knowledge, this is the first example where genetic manipulation of the stroma leads to an increased incidence of BCBM. Our pre-clinical data suggests that primary breast tumors that express high PDGFB could preferentially metastasize to the brain. To test this in patients, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple negative BC primary tumors. While high PDGFB did not correlate with site-independent metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Our findings suggest that high primary tumor PDGFB expression defines a subset of BC patients predisposed to brain metastases. These patients may benefit from therapeutic intervention of PDGFRβ signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the PDGFR-specific inhibitor, crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice. Combined, our findings (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM.

A common goal to CARE: Cancer Advocates, Researchers, and Clinicians Explore current treatments and clinical trials for breast cancer brain metastases

npj Breast Cancer ◽

10.1038/s41523-021-00326-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Natalie S. Joe ◽

Christine Hodgdon ◽

Lianne Kraemer ◽

Kristin J. Redmond ◽

Vered Stearns ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Brain Metastases ◽

Detection Methods ◽

Future Research ◽

Breast Cancer Brain Metastasis ◽

Patient Advocates ◽

Breast Cancer Brain Metastases ◽

AbstractBreast cancer is the most commonly diagnosed cancer in women worldwide. Approximately one-tenth of all patients with advanced breast cancer develop brain metastases resulting in an overall survival rate of fewer than 2 years. The challenges lie in developing new approaches to treat, monitor, and prevent breast cancer brain metastasis (BCBM). This review will provide an overview of BCBM from the integrated perspective of clinicians, researchers, and patient advocates. We will summarize the current management of BCBM, including diagnosis, treatment, and monitoring. We will highlight ongoing translational research for BCBM, including clinical trials and improved detection methods that can become the mainstay for BCBM treatment if they demonstrate efficacy. We will discuss preclinical BCBM research that focuses on the intrinsic properties of breast cancer cells and the influence of the brain microenvironment. Finally, we will spotlight emerging studies and future research needs to improve survival outcomes and preserve the quality of life for patients with BCBM.

AKT1 is differentially expressed in primary tumors and brain metastases in humans with breast cancer.

10.31219/osf.io/m2ubf ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Central Nervous System Metastasis ◽

Human Breast ◽

Primary Tumors ◽

Breast Tissues ◽

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We report here the differential expression of the protein kinase AKT1 in the primary tumors and brain metastases of humans with breast cancer. AKT1 mRNA was present at significantly increased quantities in brain metastatic tissues as compared to primary tumors of the breast. These data combined suggest that up-regulation of AKT1 is a conserved event, both during transformation of breast tissues and progression to central nervous system metastasis and further point to potential importance of AKT1 modulation during progression of human breast cancer.

MMP13 is differentially expressed and down-regulated in brain metastatic breast cancer.

10.31219/osf.io/hx2ur ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Metastatic Breast ◽

Clinical Problem ◽

Differentially Expressed ◽

Gene Encoding ◽

Matrix Metalloproteinase 13 ◽

The Matrix ◽

Brain metastases are a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to discover genes associated with brain metastasis in patients with brain metastatic breast cancer. We found that the gene encoding the matrix metalloproteinase 13, MMP13, was among the genes most differentially expressed in the brain metastases of patients with brain metastatic breast cancer. MMP13 may be of relevance to the biology underlying metastasis to the brain in humans with metastatic breast cancer. MMP13 now joins MMP14, MMP11 and MMP2 among matrix metalloproteinases we have found to be differentially expressed and down-regulated in the brain metastases of humans with metastatic breast cancer (6-8).

FGF12 is differentially expressed in the brain metastases of patients with metastatic breast cancer.

10.31219/osf.io/7e5wd ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Normal Breast ◽

Primary Tumors ◽

Breast Tissues ◽

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that the fibroblast growth factor 12, encoded by FGF12, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to normal breast tissues. FGF12 mRNA expression was significantly higher in brain metastatic tissues as compared to primary tumors of the breast. Up-regulation of FGF12 expression may contribute to metastasis of tumor cells from the breast to the brain in humans with metastatic breast cancer.

C1R is differentially expressed in the brain metastases of patients with metastatic breast cancer.

10.31219/osf.io/p9eyr ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Normal Breast ◽

Primary Tumors ◽

Breast Tissues ◽

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that the complement component 1, r subcomponent, encoded by C1R, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to normal breast tissues. C1R mRNA was present at significantly reduced quantities in brain metastatic tissues as compared to primary tumors of the breast. Down-regulation of C1R expression may contribute to metastasis of tumor cells from the breast to the brain in humans with metastatic breast cancer.

TTF1 is a differentially expressed gene in both lymph node and brain metastases in human breast cancer.

10.31219/osf.io/cjksh ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Brain Metastases ◽

Differentially Expressed Gene ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Primary Tumors ◽

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that transcription termination factor 1, encoded by TTF1, was among the genes whose expression was most quantitatively different in the brain metastases of patients with metastatic breast cancer. TTF1 mRNA was present at decreased quantities in brain metastatic tissues as compared to primary tumors of the breast. Importantly, expression of TTF1 in primary tumors was significantly correlated with patient distant metastasis-free survival in patients with breast cancer. Modulation of TTF1 expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain. These data are one piece of evidence suggesting a common ancestor or tumor clone for brain and lymph node metastases that originate from the primary tumor, alluding to patterns in developmental origin and migratory pathways through the lymph node in human brain metastatic breast cancer.

Palladin is differentially expressed in both lymph node and brain metastases in human breast cancer.

10.31219/osf.io/24u98 ◽

2021 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Human Breast Cancer ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Human Breast ◽

Primary Tumors ◽

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that palladin, encoded by PALLD, was among the genes whose expression was most quantitatively different in the brain metastases of patients with metastatic breast cancer. PALLD mRNA was present at decreased quantities in brain metastatic tissues as compared to primary tumors of the breast. Importantly, expression of PALLD in primary tumors was significantly correlated with patient overall survival in patients with breast cancer. Modulation of PALLD expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain.