James Alvarez

Positions:

Assistant Professor of Pharmacology & Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1999

Pennsylvania State University

Ph.D. 2005

Harvard Medical School

Grants:

Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Pathways regulating dormant cell survival and recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Defining the role of the histone methyltransferase G9a in mitigating replication stress in cancer

Administered By
Pharmacology & Cancer Biology
Awarded By
Howard Hughes Medical Institute
Role
Principal Investigator
Start Date
End Date

Par-4 Regulation and Function in Breast Cancer Dormancy and Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.

The survival and recurrence of dormant tumour cells following therapy is a leading cause of death in cancer patients. The metabolic properties of these cells are likely distinct from those of rapidly growing tumours. Here we show that Her2 down-regulation in breast cancer cells promotes changes in cellular metabolism, culminating in oxidative stress and compensatory upregulation of the antioxidant transcription factor, NRF2. NRF2 is activated during dormancy and in recurrent tumours in animal models and breast cancer patients with poor prognosis. Constitutive activation of NRF2 accelerates recurrence, while suppression of NRF2 impairs it. In recurrent tumours, NRF2 signalling induces a transcriptional metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. The NRF2-driven metabolic state renders recurrent tumour cells sensitive to glutaminase inhibition, which prevents reactivation of dormant tumour cells in vitro, suggesting that NRF2-high dormant and recurrent tumours may be targeted. These data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer.
Authors
Fox, DB; Garcia, NMG; McKinney, BJ; Lupo, R; Noteware, LC; Newcomb, R; Liu, J; Locasale, JW; Hirschey, MD; Alvarez, JV
MLA Citation
Fox, Douglas B., et al. “NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism.Nat Metab, vol. 2, no. 4, Apr. 2020, pp. 318–34. Pubmed, doi:10.1038/s42255-020-0191-z.
URI
https://scholars.duke.edu/individual/pub1437935
PMID
32691018
Source
pubmed
Published In
Nature Metabolism
Volume
2
Published Date
Start Page
318
End Page
334
DOI
10.1038/s42255-020-0191-z

Optical Imaging of Glucose Uptake and Mitochondrial Membrane Potential to Characterize Her2 Breast Tumor Metabolic Phenotypes.

With the large number of women diagnosed and treated for breast cancer each year, the importance of studying recurrence has become evident due to most deaths from breast cancer resulting from tumor recurrence following therapy. To mitigate this, cellular and molecular pathways used by residual disease prior to recurrence must be studied. An altered metabolism has long been considered a hallmark of cancer, and several recent studies have gone further to report metabolic dysfunction and alterations as key to understanding the underlying behavior of dormant and recurrent cancer cells. Our group has used two probes, 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG) and tetramethyl rhodamine ethyl ester (TMRE), to image glucose uptake and mitochondrial membrane potential, respectively, to report changes in metabolism between primary tumors, regression, residual disease, and after regrowth in genetically engineered mouse (GEM)-derived mammospheres. Imaging revealed unique metabolic phenotypes across the stages of tumor development. Although primary mammospheres overexpressing Her2 maintained increased glucose uptake ("Warburg effect"), after Her2 downregulation, during regression and residual disease, mammospheres appeared to switch to oxidative phosphorylation. Interestingly, in mammospheres where Her2 overexpression was turned back on to model recurrence, glucose uptake was lowest, indicating a potential change in substrate preference following the reactivation of Her2, reeliciting growth. Our findings highlight the importance of imaging metabolic adaptions to gain insight into the fundamental behaviors of residual and recurrent disease. IMPLICATIONS: This study demonstrates these functional fluorescent probes' ability to report metabolic adaptations during primary tumor growth, regression, residual disease, and regrowth in Her2 breast tumors.
Authors
Madonna, MC; Fox, DB; Crouch, BT; Lee, J; Zhu, C; Martinez, AF; Alvarez, JV; Ramanujam, N
MLA Citation
Madonna, Megan C., et al. “Optical Imaging of Glucose Uptake and Mitochondrial Membrane Potential to Characterize Her2 Breast Tumor Metabolic Phenotypes.Mol Cancer Res, vol. 17, no. 7, July 2019, pp. 1545–55. Pubmed, doi:10.1158/1541-7786.MCR-18-0618.
URI
https://scholars.duke.edu/individual/pub1375682
PMID
30902832
Source
pubmed
Published In
Mol Cancer Res
Volume
17
Published Date
Start Page
1545
End Page
1555
DOI
10.1158/1541-7786.MCR-18-0618

Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.

Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.
Authors
Chen, C-C; Stairs, DB; Boxer, RB; Belka, GK; Horseman, ND; Alvarez, JV; Chodosh, LA
MLA Citation
Chen, Chien-Chung, et al. “Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways.Genes Dev, vol. 26, no. 19, Oct. 2012, pp. 2154–68. Pubmed, doi:10.1101/gad.197343.112.
URI
https://scholars.duke.edu/individual/pub1116150
PMID
23028142
Source
pubmed
Published In
Genes Dev
Volume
26
Published Date
Start Page
2154
End Page
2168
DOI
10.1101/gad.197343.112

Oncogene addiction: Mouse models and clinical relevance for molecularly targeted therapies

© 2012, Springer Science+Business Media, LLC. All rights reserved. Cancer results from the dysregulation of pathways controlling the growth, proliferation, differentiation, and survival of tumor cells, as well as fundamental alterations in the manner in which cells interact with their microenvironment (Hanahan and Weinberg 2000). Several lines of evidence suggest that these alterations are due to the accumulation of multiple mutations in oncogenes and tumor suppressor genes that disrupt their normal function or regulation. These mutations provide a selective advantage to the cells in which they occur, leading to their expansion and clinical manifestation as a tumor.
Authors
Alvarez, JV; Yeh, ES; Feng, Y; Chodosh, LA
MLA Citation
Alvarez, J. V., et al. Oncogene addiction: Mouse models and clinical relevance for molecularly targeted therapies. Jan. 2012, pp. 527–47. Scopus, doi:10.1007/978-0-387-69805-2_25.
URI
https://scholars.duke.edu/individual/pub1116151
Source
scopus
Published Date
Start Page
527
End Page
547
DOI
10.1007/978-0-387-69805-2_25

Akt is required for Stat5 activation and mammary differentiation.

INTRODUCTION: The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2-deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. METHODS: In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. RESULTS: Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. CONCLUSIONS: Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.
Authors
Chen, C-C; Boxer, RB; Stairs, DB; Portocarrero, CP; Horton, RH; Alvarez, JV; Birnbaum, MJ; Chodosh, LA
MLA Citation
Chen, Chien-Chung, et al. “Akt is required for Stat5 activation and mammary differentiation.Breast Cancer Res, vol. 12, no. 5, 2010, p. R72. Pubmed, doi:10.1186/bcr2640.
URI
https://scholars.duke.edu/individual/pub1116152
PMID
20849614
Source
pubmed
Published In
Breast Cancer Res
Volume
12
Published Date
Start Page
R72
DOI
10.1186/bcr2640