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:

Awakening the dormant tumor: the role of the tumor microenvironment in breast cancer recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
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

The Role of Epigenetic Plasticity in Breast Cancer Recurrence

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Pathways regulating dormant cell survival and recurrence

Administered By
Pharmacology & Cancer Biology
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
Co Investigator
Start Date
End Date

Publications:

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

SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling.

UNLABELLED: Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer. SIGNIFICANCE: The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1-c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacologic targets for recurrence may be unique to this stage of tumor progression.
Authors
Feng, Y; Pan, T-C; Pant, DK; Chakrabarti, KR; Alvarez, JV; Ruth, JR; Chodosh, LA
MLA Citation
Feng, Yi, et al. “SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling..” Cancer Discov, vol. 4, no. 7, July 2014, pp. 790–803. Pubmed, doi:10.1158/2159-8290.CD-13-0548.
URI
https://scholars.duke.edu/individual/pub1116149
PMID
24786206
Source
pubmed
Published In
Cancer Discov
Volume
4
Published Date
Start Page
790
End Page
803
DOI
10.1158/2159-8290.CD-13-0548

Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy.

Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.
Authors
Alvarez, JV; Pan, T-C; Ruth, J; Feng, Y; Zhou, A; Pant, D; Grimley, JS; Wandless, TJ; Demichele, A; I-SPY 1 TRIAL Investigators,; Chodosh, LA
MLA Citation
Alvarez, James V., et al. “Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy..” Cancer Cell, vol. 24, no. 1, July 2013, pp. 30–44. Pubmed, doi:10.1016/j.ccr.2013.05.007.
URI
https://scholars.duke.edu/individual/pub1116148
PMID
23770012
Source
pubmed
Published In
Cancer Cell
Volume
24
Published Date
Start Page
30
End Page
44
DOI
10.1016/j.ccr.2013.05.007

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