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FOXC1 Is a Potential Prognostic Biomarker with Functional Significance in Basal-like Breast Cancer

Partha S. Ray, Jinhua Wang, Ying Qu, Myung-Shin Sim, Jaime Shamonki, Sanjay P.Bagaria, Xing Ye, Bingya Liu, David Elashoff, Dave S. Hoon, Michael A. Walter, John W.Martens, Andrea L. Richardson, Armando E. Giuliano and Xiaojiang Cui

Cancer Res May 15 2010 (70) (10) 3870-3876; DOI: 10.1158/0008-5472.CAN-09-4120

Gene expression signatures for a basal-like breast cancer (BLBC) subtype have been associated with poor clinical outcomes, but a molecular basis for this disease remains unclear. Here, we report overexpression of the transcription factor FOXC1 as a consistent feature of BLBC compared with other molecular subtypes of breast cancer. Elevated FOXC1 expression predicted poor overall survival in BLBC (P = 0.0001), independently of other clinicopathologic prognostic factors including lymph node status, along with a higher incidence of brain metastasis (P = 0.02) and a shorter brain metastasis–free survival in lymph node–negative patients (P < 0.0001). Ectopic overexpression of FOXC1 in breast cancer cells increased cell proliferation, migration, and invasion, whereas shRNA-mediated FOXC1 knockdown yielded opposite effects. Our findings identify FOXC1 as a theranostic biomarker that is specific for BLBC, offering not only a potential prognostic candidate but also a potential molecular therapeutic target in this breast cancer subtype. Cancer Res; 70(10); 3870–6. ©2010 AACR.

[2010] Ray: FOXC1 is a potential prognostic biomarker with functional significance in BLBC

Basal-like breast cancer defined by FOXC1 expression offers superior prognostic value: a retrospective immunohistochemical study.

Ray PSBagaria SPWang JShamonki JMYe XSim MSSteen SQu YCui XGiuliano AE.

Ann Surg Oncol. 2011 Dec;18(13):3839-47. doi: 10.1245/s10434-011-1657-8. Epub 2011 Mar 18.

BACKGROUND:

Basal-like breast cancer (BLBC) has a poor prognosis and is often identified by the triple-negative phenotype (TNP) and/or basal cytokeratins (CKs). Overexpression of mRNA for forkhead box C1 (FOXC1) transcription factor was recently identified as a pivotal prognostic biomarker of BLBC. We investigated the prognostic value of FOXC1 protein expression in invasive breast cancer and compared its prognostic significance to that of TNP and basal CKs.

METHODS:

Archived TNP specimens of primary invasive ductal breast cancer from 759 patients were examined by immunohistochemical staining for FOXC1, CK5/6, and CK14; prognostic significance was assessed using multivariate analyses. In addition, the impact of adding FOXC1 versus basal CKs to TNP-based BLBC assessment was assessed.

RESULTS:

FOXC1 protein expression was a significant predictor of overall survival on univariate (hazard ratio [HR] 3.364 95% confidence interval [CI] 1.758-6.438, P = 0.0002) and multivariate (HR 3.389 95% CI 1.928-7.645, P = 0.0001) analyses, despite its correlation with younger age (P = 0.0003). Interestingly, nodal status was not significant on multivariate analysis when FOXC1 expression status was included in the analysis. BLBC defined by TNP plus FOXC1 demonstrated superior prognostic relevance compared to BLBC defined by TNP or TNP plus basal CKs.

CONCLUSIONS:

Immunohistochemical detection of FOXC1 expression in TNP invasive breast cancer is an independent prognostic indicator that is superior to conventional immunohistochemical surrogates of BLBC. Prospective validation is warranted to further define the diagnostic, prognostic, and predictive utility of FOXC1 in breast cancer management and clinical trial design.

[2011] Ray: Basal-like breast cancer defined by FOXC1 expression offers superior prognostic value

FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling.

Wang J1, Ray PSSim MSZhou XZLu KPLee AVLin XBagaria SPGiuliano AECui X.

Oncogene. 2012 Nov 8;31(45):4798-802. doi: 10.1038/onc.2011.635. Epub 2012 Jan 16.

Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BLBC cells by increasing p65/RelA protein stability. High NF-κB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-κB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-κB. These results suggest that BLBC cells may rely on FOXC1-driven NF-κB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.

[2012] Wang: FOXC1 regulates the functions of human basal-like breast cancer cells by activating N..

FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer*

Yanli Jin, PhD, Bingchen Han, PhD, Jiongyu Chen, BS, Ruprecht Wiedemeyer, PhD, Sandra Orsulic, PhD, Shikha Bose, MD, Xiao Zhang, PhD, S Beth, Y. Karlan, MD, Armando E. Giuliano, MD, Yukun Cui, PhD, and Xiaojiang Cui, PhD**

Ann Surg Oncol. 2014 Dec;21 Suppl 4:S758-66. doi: 10.1245/s10434-014-3980-3

* Research not sponsored by the Company.

  Substantial investigation citing prior Company-related research.

** Xiaojiang Cui, PhD:  Company Consultant and Inventor on certain Company patent filings.

BACKGROUND:

Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear.

METHODS:

The association between FOXC1 and EGFR expression in human breast cancer was examined by immunohistochemistry in formalin-fixed tissues and analysis of the TCGA database. The regulation of FOXC1 by EGFR activation was investigated in MDA-MB-468 cells using immunoblotting, qRT-PCR, and luciferase activity assays. This EGFR effect on FOXC1 expression was confirmed using the MDA-MB-468 xenograft model.

RESULTS:

Both FOXC1 mRNA and protein levels significantly correlated with EGFR expression in human breast tumors. EGFR activation induced FOXC1 transcription through the ERK and Akt pathways in BLBC. EGFR inhibition in vivo reduced FOXC1 expression in xenograft tumors. We also found that FOXC1 knockdown impaired the effects of EGF on BLBC cell proliferation, migration, and invasion.

CONCLUSIONS:

Our findings uncover a novel EGFR-FOXC1 signaling axis critical for BLBC cell functions, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.

[2014] Yanli: FOXC1 is a critical mediator of EGFR function in human basal-like breast cancer

Diagnosis of Basal-Like Breast Cancer Using a FOXC1-Based Assay

Tor W. Jensen, Tania Ray, Jinhua Wang, Xiaodong Li,  Wesley Y. Naritoku, Bingchen Han, Frank Bellafiore,  Sanjay P. Bagaria, Annie Qu, Xiaojiang Cui, Clive R. Taylor, Partha S. Ray

JNCI J Natl Cancer Inst (2015) 107(8): djv148

Background:

Diagnosis of basal-like breast cancer (BLBC) remains a bottleneck to conducting effective clinical trials for this aggressive subtype. We postulated that elevated expression of Forkhead Box transcription factor C1 (FOXC1) is a simple and accurate diagnostic biomarker for BLBC.

Methods:

Accuracy of FOXC1 expression in identifying BLBC was compared with the PAM50 gene expression panel in gene expression microarray (GEM) (n = 1992) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 349) datasets. A FOXC1-based immunohistochemical (IHC) assay was developed and assessed in 96 archival formalin-fixed, paraffin-embedded (FFPE) breast cancer samples that also underwent PAM50 profiling. All statistical tests were two-sided.

Results:

A FOXC1-based two-tier assay (IHC +/- qRT-PCR) accurately identified BLBC (AUC = 0.88) in an independent cohort of FFPE samples, validating the accuracy of FOXC1-defined BLBC in GEM (AUC = 0.90) and qRT-PCR (AUC = 0.88) studies, when compared with platform-specific PAM50-defined BLBC. The hazard ratio (HR) for disease-specific survival in patients having FOXC1-defined BLBC was 1.71 (95% CI = 1.31 to 2.23, P < .001), comparable to PAM50 assay-defined BLBC (HR = 1.74, 95% CI = 1.40 to 2.17, P < .001). FOXC1 expression also predicted the development of brain metastasis. Importantly, unlike triple-negative or Core Basal IHC definitions, a FOXC1-based definition is able to identify BLBC in both ER+ and HER2+ patients.

Conclusion:

A FOXC1-based two-tier assay, by virtue of being rapid, simple, accurate, and cost-effective may emerge as the diagnostic assay of choice for BLBC. Such a test could substantially improve clinical trial enrichment of BLBC patients and accelerate the identification of effective chemotherapeutic options for this aggressive disease.

[2015] Jensen: Diagnosis of basal-like breast cancer using a FOXC1-based assay

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

B Han, Y Qu, Y Jin, Y Yu, N Deng, K Wawrosky, X Zhang, N Li, S Bose, Q Wang, S Sakkiah, R. Abrol, TW Jensen, B Bereman, H Tanaka, J Johnson, B Gao, J Hao, Z Liu, R Buttyan, PS Ray, MC Hung, A Giuliano, X Cui

Han et al., 2015, Cell Reports 13, 1046–105

The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here, we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. Furthermore, we show that the N-terminal domain of FOXC1 (aa 1–68) binds directly to an internal region (aa 898–1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.

[2015A] Han: FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated in endocrine resistance.*

Yu-Rice Y, Jin Y, Han B, Qu Y, Johnson J, Watanabe T, Cheng L, Deng N, Tanaka H, Gao B, Liu Z, Sun Z, Bose S, Giuliano AE, Cui X.** 

Oncogene. 2016 Oct 13;35(41):5400-5411. doi: 10.1038/onc.2016.78. Epub 2016 Apr 4

 

* Research not sponsored by the Company.

  Investigation citing prior Company-related research.

** Xiaojiang Cui, PhD:  Company Consultant and Inventor on certain Company patent filings.

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Estrogen receptor-α (ERα) mediates the essential biological function of estrogen in breast development and tumorigenesis. Multiple mechanisms, including pioneer factors, coregulators, and epigenetic modifications have been identified as regulators of ERα signaling in breast cancer. However, previous studies of ERα regulation have focused on luminal and HER2-positive subtypes rather than basal-like breast cancer (BLBC), in which ERα is underexpressed. In addition, mechanisms that account for the decrease or loss of ER expression in recurrent tumors after endocrine therapy remain elusive. Here, we demonstrate a novel FOXC1-driven mechanism that suppresses ERα expression in breast cancer. We find that FOXC1 competes with GATA3 for the same binding regions in the cis-regulatory elements (CREs) upstream of the ERα gene and thereby downregulates ERα expression and consequently its transcriptional activity. The forkhead domain of FOXC1 is essential for the competition with GATA3 for DNA binding. Counteracting the action of GATA3 at the ERα promoter region, overexpression of FOXC1 hinders recruitment of RNA polymerase II and increases histone H3K9 trimethylation at ERα promoters. Importantly, ectopic FOXC1 expression in luminal breast cancer cells reduces sensitivity to estrogen and tamoxifen. Furthermore, in breast cancer patients with ER-positive primary tumors who received adjuvant tamoxifen treatment, FOXC1 expression is associated with decreased or undetectable ER expression in recurrent tumors. Our findings highlight a clinically relevant mechanism that contributes to the low or absent ERα expression in BLBC. This study suggests a new paradigm to study ERα regulation during breast cancer progression and indicates a role of FOXC1 in the modulation of cellular response to endocrine treatment

[2016] Yu-Rice: FOXC1 is involved in ERα silencing by counteracting GATA3 binding and is implicated

FOXC1 identifies basal-like breast cancer in a hereditary breast cancer cohort*

Johnson, J., Choi, M., Dadmanesh, F., Han, B., Qu, Y., Yu-Rice, Y., … Cui, X.**  (Nov 2016). Oncotarget, 7(46), 75729–75738. http://doi.org/10.18632/oncotarget.12370

 

* Research not sponsored by the Company.

  Substantial investigation citing prior Company-related research.

  Collaborators involved in Cancer Research Landmark Study Publication 2010

** Xiaojiang Cui, PhD:  Company Consultant and Inventor on certain Company patent filings.

Breast cancers arising in the setting of the hereditary breast cancer genes BRCA1 and BRCA2 are most commonly classified as basal-like breast cancer (BLBC) or luminal breast cancer, respectively. BLBC is an aggressive subtype of breast cancer associated with liver and lung metastases and poorer prognosis than other subtypes and for which chemotherapy is the only systemic therapy. Multiple immunohistochemical markers are used to identify the basal-like subtype, including the absence of estrogen receptor alpha, progesterone receptor, and human epidermal growth factor receptor 2. Forkhead box C1 (FOXC1) has been identified as a specific marker expressed in BLBC in general breast cancer cohorts. We examined an institutional cohort of breast cancer patients with germline BRCA1 (n=46) and BRCA2 (n=35) mutations and found that FOXC1 expression on immunohistochemical staining is associated with BRCA1 vs BRCA2 mutations [30/46 vs. 6/35]. In BRCA1 mutant tumors, FOXC1 was expressed in 28/31 BLBC tumors and 2/13 non-BLBC tumors, In BRCA2 mutant tumors, FOXC1 was expressed in 5/5 BLBC tumors and 1/30 non-BLBC tumors. In cell culture models of BRCA1-mutant breast cancer, FOXC1 is associated with increased proliferation and may serve as a marker for sensitivity to PARP-inhibitor therapy with olaparib.

[2016A] Johnson FOXC1 identifies basal-like breast cancer in a hereditary breast cancer cohort
[2017] Wang: FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen

FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer

Jinhua Wang,* Yali Xu, Li Li, Lin Wang, Ru Yao, Qiang Sun & Guanhua Dui

Cancer Medicine 2017; 6(1):275–287  doi: 10.1002/cam4.990

* Research not sponsored by the Company.

  Collaborator involved in Cancer Research Landmark Study Publication 2010

  Substantial investigation with Company while at the John Wayne Cancer Institute​

cam4.v9.2.cover.jpg

FOXC1 is a member of Forkhead box transcription factors that participates in embryonic development and tumorigenesis. Our previous study demonstrated that FOXC1 was highly expressed in triple- negative breast cancer. However, it remains unclear what is the relation between FOXC1 and ERα and if FOXC1 regulates expression of ERα. To explore relation between FOXC1 and ERα and discover regulation of ERα expression by FOXC1 in breast cancer, we analyzed data assembled in the Oncomine and TCGA, and found that there was significantly higher FOXC1 expression in estrogen receptor- negative breast cancer than that in estrogen receptor- positive breast cancer. Overexpression of FOXC1 reduced expression of ERα and cellular responses to estradiol (E2) and tamoxifen in the MCF- 7 FOXC1 and T47D FOXC1 cells, while knockdown of FOXC1 induced expression of ERα and improved responses to estradiol (E2) and tamoxifen in BT549 FOXC1 shRNA and HCC1806 FOXC1 shRNA cells. In addition, overexpression of FOXC1 reduced expression of progesterone receptor (PR), Insulin receptor substrate 1 (IRS1), and XBP1 (X- Box Binding Protein 1) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay. These results suggested that FOXC1 regulated expression of ERα and affected sensitivity of tamoxifen treatment in breast cancer, and that FOXC1 may be used as a potential therapeutic target in ERα- negative breast cancer.

Identification of EGF-NF-κB-FOXC1 signaling axis in basal-like breast cancer. *

 

Chung S, Jin Y, Han B, Qu Y, Gao B, Giuliano AE, Cui X.** Cell Commun Signal. 2017 Jun 19;15(1):22. doi: 10.1186/s12964-017-0180-3. PMID: 28629477; PMCID: PMC5477115.

Identification of EGF-NF-κB-FOXC1 signaling axis in basal-like breast cancer

* Research not sponsored by the Company.

  Collaborators involved in Cancer Research Landmark Study Publication 2010

** Xiaojiang Cui, PhD:  Company Consultant and Inventor on certain Company patent filings.

 

BACKGROUND:

The pathogenesis of human basal-like breast cancer (BLBC) is not well understood and patients with BLBC have a poor prognosis. Expression of the epidermal growth factor receptor (EGFR) and nuclear factor-κB (NF-κB) is well-known to be upregulated in BLBC. The forkhead box C1 (FOXC1) transcription factor, an important prognostic biomarker specific for BLBC, has been shown to be induced by EGF and is critical for EGF effects in breast cancer cells. How FOXC1 is transcriptionally activated in BLBC is not clear.

METHODS:

Luciferase reporter assays were performed to show that NF-κB-p65 enhances FOXC1 promoter activity in BLBC cells (MDA-MB-468). Electrophoretic mobility shift assay, biotinylated oligonucleotide precipitation assay, and chromatin immunoprecipitation assay were used to show that NF-κB interacts and binds to the promoter region of FOXC1.

RESULTS:

In this study, we demonstrate that NF-κB is a pivotal mediator of the EGF/EGFR regulation of FOXC1 expression by binding to the FOXC1 promoter to activate FOXC1 transcription. Loss or inhibition of NF-κB diminished FOXC1 expression.

CONCLUSION:

Collectively, our findings reveal a novel EGFR-NF-κB-FOXC1 signaling axis that is critical for BLBC cell function, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.

KEYWORDS:

Basal-like breast cancer; Epidermal growth factor; FOXC1; NF-κB

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[2017A] Chung: Identification of EGF-NF-κB-FOXC1 signaling axis in basal-like breast cancer

Inhibition of lobuloalveolar development by FOXC1 overexpression in the mouse mammary gland*

Bowen Gao, Ying Qu, Bingchen Han, Yoshiko Nagaoka, Makoto Katsumata, Nan Deng, Shikha Bose, Liting Jin, Armando E. Giuliano & Xiaojiang Cui*  Nature/Scientific Reports.  Oct 2017:1 Retrieved on

 

* Research not sponsored by the Company.

  Substantial investigation citing prior Company-related research.

  Collaborators involved in Cancer Research Landmark Study Publication 2010

** Xiaojiang Cui, PhD:  Company Consultant and Inventor on certain Company patent filings.

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The forkhead box transcription factor FOXC1 plays a critical role in embryogenesis and the development of many organs. Its mutations and high expression are associated with many human diseases including breast cancer. Although FOXC1 knockout mouse studies showed that it is not required for mammary gland development during puberty, it is not clear whether its overexpression alters normal mammary development in vivo. To address this question, we generated transgenic mice with mammary-specifc FOXC1 overexpression. We report that transgenic FOXC1 overexpression suppresses lobuloalveologenesis and lactation in mice. This phenotype is associated with higher percentages of estrogen receptor-, progesterone receptor-, or ki67-positive mammary epithelial cells in the transgenic mice at the lactation stage. We also show that expression of the Elf5 transcription factor, a master regulator of mammary alveologenesis and luminal cell diferentiation, is markedly reduced in mammary epithelial cells of transgenic mice. Likewise, levels of activated Stat5, another inducer of alveolar expansion and a known mediator of the Elf5 efect, are also lowered in those cells. In contrast, the cytokeratin 8-positive mammary cell population with progenitor properties is elevated in the transgenic mice at the lactation stage, suggesting inhibition of mammary cell diferentiation. These results may implicate FOXC1 as a new important regulator of mammary gland development.

[2017B] GAO: Inhibition of lobuloalveolar development by FOXC1 overexpression in the mouse mammary gland
[2017C] Swaminathan: FOXC1 Expression in Acute Myeloid Leukemia: Potential Predictor of Disease

FOXC1 Expression in Acute Myeloid Leukemia: Potential Predictor of Disease Relapse and/or Refractory Disease

Swaminathan M, Jensen TW, Ray T, Andruska N, Shah A, Egner JR, Ray PS  

Blood,128(22), 5260. Accessed December 10, 2017. Retrieved from http://www.bloodjournal.org/content/128/22/5260.

The mesenchymal transcription factor Forkhead Box C1 (FOXC1), derepressed in hematopoietic stem progenitor cells (HSPCs) in the setting of acute myeloid leukemia (AML), but not in normal HSPCs, was recently demonstrated to play an important role in AML disease onset and progression by blocking myeloid lineage differentiation and enhancing clonogenic potential. Herein we sought to further examine the prognostic value of FOXC1 in AML and whether FOXC1 expression is a potential predictor of disease relapse and/or lack of response to induction chemotherapy in AML.

[2017D] Han: FOXC1: An emerging marker and therapeutic target for cancer

FOXC1: an emerging marker and therapeutic target for cancer*

Han, B., Bhowmick, N., Qu, Y., Chung, S., Giuliano, A. E., & Cui, X.** (2017).

Oncogene, 36(28), 3957–3963. http://doi.org/10.1038/onc.2017.48 Accessed on 1/16/2018

* Research not sponsored by the Company.

  Substantial investigation citing prior Company-related research.

** Xiaojiang Cui, PhD:  Company Consultant and Inventor on certain Company patent filings.

The Forkhead box C1 (FOXC1) transcription factor is involved in normal embryonic development and regulates the development and function of many organs. Most recently, a large body of literature has shown that FOXC1 plays a critical role in tumor development and metastasis. Clinical studies have demonstrated that elevated FOXC1 expression is associated with poor prognosis in many cancer subtypes, such as basal-like breast cancer (BLBC). FOXC1 is highly and specifically expressed in BLBC as opposed to other breast cancer subtypes. Its functions in breast cancer have been extensively explored. This review will summarize current knowledge on the function and regulation of FOXC1 in tumor development and progression with a focus on BLBC as well as the implications of these new findings in cancer diagnosis and treatment.

Basal - Like Breast Cancer: Signal Review

Ray PS, Fagnani, R

European Biopharmaceutical Review Autumn  October 2017 (pages10-12).   Retrieved from http://www.samedanltd.com/magazine/12/issue/278  on 1/2/18 © Samedan Ltd

These studies demonstrated that the presence of FOXC1 is capable of detecting BLBC with sensitivity and specificity via standard IHC staining of breast tissue slides.

[2018] Ray: Basal - Like Breast Cancer: Signal Review
[2020] Emad: Superior breast cancer metastasis risk stratification using an epithelial mesenchymal-amoeboid

Superior breast cancer metastasis risk stratification using an epithelial mesenchymal-amoeboid transition gene signature

Amin Emad, Tania Ray, Tor W. Jensen, Meera Parat, Rachael Natrajan, Saurabh Sinha and Partha S. Ray

Breast Cancer Res 22, 74 (2020). https://doi.org/10.1186/s13058-020-01304-8

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Background: Cancer cells are known to display varying degrees of metastatic propensity, but the molecular basis underlying such heterogeneity remains unclear. Our aims in this study were to (i) elucidate prognostic subtypes in primary tumors based on an epithelial-to-mesenchymal-to-amoeboid transition (EMAT) continuum that captures the heterogeneity of metastatic propensity and (ii) to more comprehensively define biologically informed subtypes predictive of breast cancer metastasis and survival in lymph node-negative (LNN) patients. Methods: We constructed a novel metastasis biology-based gene signature (EMAT) derived exclusively from cancer cells induced to undergo either epithelial-to-mesenchymal transition (EMT) or mesenchymal-to-amoeboid transition (MAT) to gauge their metastatic potential. Genome-wide gene expression data obtained from 913 primary tumors of lymph node-negative breast cancer (LNNBC) patients were analyzed. EMAT gene signature-based prognostic stratification of patients was performed to identify biologically relevant subtypes associated with distinct metastatic propensity. Results: Delineated EMAT subtypes display a biologic range from less stem-like to more stem-like cell states and from less invasive to more invasive modes of cancer progression. Consideration of EMAT subtypes in combination with standard clinical parameters significantly improved survival prediction. EMAT subtypes outperformed prognosis accuracy of receptor or PAM50-based BC intrinsic subtypes even after adjusting for treatment variables in 3 independent, LNNBC cohorts including a treatment-naïve patient cohort.

 

Conclusions: EMAT classification is a biologically informed method that provides prognostic information beyond that which can be provided by traditional cancer staging or PAM50 molecular subtype status and may improve metastasis risk assessment in early stage, LNNBC patients, who may otherwise be perceived to be at low metastasis risk.

 

Keywords: Epithelial-to-mesenchymal transition, Mesenchymal-to-amoeboid transition, Metastasis, Breast cancer subtypes, Metastatic risk assessment

[2021] Ray: Therapeutically targeting cancers that overexpress FOXC1: A transcriptional driver of...

Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

Tania Ray, Terry Ryusaki, Partha S. Ray, Frontiers in Oncology, September 3, 2021,  https://doi.org/10.3389/fonc.2021.721959

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Metastasis accounts for more than 90% of cancer related mortality, thus the most pressing need in the field of oncology today is the ability to accurately predict future onset of metastatic disease, ideally at the time of initial diagnosis. As opposed to current practice, what would be desirable is that prognostic, biomarker-based detection of metastatic propensity and heightened risk of cancer recurrence be performed long before overt metastasis has set in. Without such timely information it will be impossible to formulate a rational therapeutic treatment plan to favorably alter the trajectory of disease progression. In order to help inform rational selection of targeted therapeutics, any recurrence/metastasis risk prediction strategy must occur with the paired identification of novel prognostic biomarkers and their underlying molecular regulatory mechanisms that help drive cancer recurrence/metastasis (i.e. recurrence biomarkers). Traditional clinical factors alone (such as TNM staging criteria) are no longer adequately prognostic for this purpose in the current molecular era. FOXC1 is a pivotal transcription factor that has been functionally implicated to drive cancer metastasis and has been demonstrated to be an independent predictor of heightened metastatic risk, at the time of initial diagnosis. In this review, we present our viewpoints on the master regulatory role that FOXC1 plays in mediating cancer stem cell traits that include cellular plasticity, partial EMT, treatment resistance, cancer invasion and cancer migration during cancer progression and metastasis. We also highlight potential therapeutic strategies to target cancers that are, or have evolved to become, “transcriptionally addicted” to FOXC1. The potential role of FOXC1 expression status in predicting the efficacy of these identified therapeutic approaches merits evaluation in clinical trials.

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