Abstract Brain metastases remain a significant challenge in the treatment of breast cancer patients due to the unique environment posed by the central nervous system. A better understanding of the biology of breast cancer cells that have metastasized to the brain is required to develop improved therapies. A recent Proceedings of the National Academy of Sciences article demonstrates that breast cancer cells in the brain microenvironment express γ-aminobutyric acid (GABA)-related genes, enabling them to utilize GABA as an oncometabolite, thus gaining a proliferative advantage. In this viewpoint, we highlight these findings and their potential impact on the treatment of breast cancer brain metastases

Anders, Carey

Siegel, Marni B

Van Swearingen, Amanda E

PubMed

Amanda ED Van Swearingen

Marni B Siegel

Carey K Anders

Crossref

Breast cancer brain metastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’ transition?

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Van Swearingen et al. Breast Cancer Research 2014, 16:304http://breast-cancer-research.com/content/16/3/304VIEWPOINTBreast cancer brain metastases: evidence forneuronal-like adaptation in a ‘breast-to-brain’transition?Amanda ED Van Swearingen1, Marni B Siegel1,2 and Carey K Anders1,3*AbstractBrain metastases remain a significant challenge in thetreatment of breast cancer patients due to the uniqueenvironment posed by the central nervous system. Abetter understanding of the biology of breast cancercells that have metastasized to the brain is required todevelop improved therapies. A recent Proceedings ofthe National Academy of Sciences article demonstratesthat breast cancer cells in the brain microenvironmentexpress γ-aminobutyric acid (GABA)-related genes,enabling them to utilize GABA as an oncometabolite,thus gaining a proliferative advantage. In this viewpoint,we highlight these findings and their potential impacton the treatment of breast cancer brain metastases.metastatic primary breast cancer cells already expressproteins that are essential for the establishment of brainBreast cancer brain metastases represent aclinically unmet need and are poorly understoodBreast cancer brain metastases (BCBMs) are an increa-singly common occurrence and portend a poor progno-sis [1]. Treatment of BCBMs represents an unmetmedical need as there are currently no approved thera-pies aside from surgical resection and cranial radiation[2]. Limited systemic treatment options for BCBMs aredue, in part, to the unique challenges posed by theneural environment. Protection afforded by the blood-brain barrier produces an immune-privileged sanctuaryand prevents many systemic therapies from penetratingthe brain, affording cancer cells unique opportunities toflourish within the neural environment. The added com-plication of drug delivery to BCBMs coupled with our* Correspondence: carey_anders@med.unc.edu1Lineberger Comprehensive Cancer Center, University of North Carolina atChapel Hill, 450 West Drive, Campus Box #7295, Chapel Hill, NC 27599, USA3Department of Medicine, Division of Hematology/Oncology, University ofNorth Carolina at Chapel Hill, 170 Manning Drive, POB Room 3119, CampusBox #7305, Chapel Hill, NC 27599, USAFull list of author information is available at the end of the article© Van Swearingen et al.; license BioMed Ce6 months following its publication. After this time(http://creativecommons.org/licenses/by/4.0), whithe original work is properly credited. The Creativpublicdomain/zero/1.0/) applies to the data mad2014poor understanding of the factors unique to BCBMgrowth, metabolism, and stromal interactions continuesto hinder the development of effective therapeuticstrategies.Two major questions regarding BCBMs are (1) whatfactors optimize BCBM cells to seed and survive in thebrain microenvironment, and (2) whether the factors arepresent in the primary breast cancer cells or are ac-quired during metastasis. Among the breast cancer sub-types, HER2-enriched (HER2+) and triple-negativeprimary tumors show higher rates of brain relapse rela-tive to hormone receptor-positive tumors [3,4], suggest-ing that some innate feature(s) of primary tumor cellsmay dictate the development of brain metastases. Recentliterature suggests that, prior to reaching the brain, somemetastases, including serpins [5], matrix metallopro-teases [6,7], and αB-crystallin [8]. Once in the brain, re-cent studies have shown BCBM cells transform thesurrounding glia and neurons to create a more permis-sive microenvironment [9-11]. Of note, tumor-activatedastrocytes have been shown to play a chemo-protectiverole for brain metastases [9] and enhance cancer cellproliferation and survival [6,12]. Targeting reactive astro-cytes in the tumor microenvironment yields therapeuticbenefit in vivo by decreasing cancer cell seeding growthin the brain [13,14]. Thus, current evidence suggests thatBCBMs are the result of both primed breast cancer cellsas well as adaptation to and alteration of the brain-tumor microenvironment. Better understanding of thebrain microenvironment and its interactions with breastcancer cells are critical for the development of improvedtreatments for BCBMs.ntral Ltd. The licensee has exclusive rights to distribute this article, in any medium, for, the article is available under the terms of the Creative Commons Attribution Licensech permits unrestricted use, distribution, and reproduction in any medium, providede Commons Public Domain Dedication waiver (http://creativecommons.org/e available in this article, unless otherwise stated.Van Swearingen et al. Breast Cancer Research Page 2 of 32014, 16:304http://breast-cancer-research.com/content/16/3/304New research provides evidence for breast cancermetabolic adaptation to the unique brainmicroenvironmentA recent elegant study by Neman and colleagues [15] in-vestigated whether human BCBMs develop from primedcells in the primary tumor, or if surviving metastaticcells adapt to the brain’s unique microenvironment.The authors compare triple-negative and HER2+ primarybreast tumors, brain metastases, and representativehuman-derived cell lines. Relative to both primary tumorsand cell lines, the brain metastases exhibit increasedexpression of several components related to signalingof the inhibitory neurotransmitter γ-aminobutyric acid(GABA), including GABAA receptors, GABA transporters(vesicular GABA transporter, GABA transporter 1-3,GABA-betaine transporter, and glutamate decarboxylase),and GABA transaminase. The study demonstrates thatupregulation of GABA-related proteins enables increasedtransport and metabolism of GABA in BCBMs cells,thereby increasing cell proliferation. The BCBMs cells alsoacquire features of GABAergic interneurons, expressinginterneuron-specific markers like parvalbumin and reelin,characteristics not seen in the primary tumors.Future treatments should target the permissivebrain microenvironment and the resultingadaptations in addition to breast cancer cellsthemselvesThis work represents one of the few studies that directlycompares human primary breast tumors with brain me-tastases (rather than assessing brain metastases aloneand/or breast cancer cell lines in vitro or in mousemodels) to identify novel factors involved in BCBM bio-logy. These results also add to a growing body of evi-dence showing a ‘breast-to-brain’ transition with cancercells adapting to the unique brain microenvironmentand acquiring neuronal characteristics that are not seenat either the primary and/or other non-brain metastaticsites [16]. The possibility remains, however, that a smallpopulation of ‘seed’ cells in primary tumors are primedfor brain metastases with additional adaptations thatoccur in the brain microenvironment ‘soil’ [17,18].The acquisition of a novel, neuronal-like GABA shuntmetabolism by the BCBM cells is one of the mostgroundbreaking findings of Neman and colleagues’ art-icle. Cancer cells can exhibit a glycolytic, Warburg-likemetabolism instead of oxidative phosphorylation as seenin normal tissues [19]; the GABA shunt in BCBMs re-flects yet another metabolic and proliferative advantageutilized by breast cancer cells within the neural environ-ment by providing additional energy through generationof nicotinamide adenine dinucleotide. This acquiredmetabolism may provide a unique target for brain me-tastases using therapies that inhibit GABA metabolism.Notably, several inhibitors of GABA are approved in theclinical setting for treatment of epilepsy [20]; however,careful research is required to determine whether selec-tively targeting this oncometabolite in the setting ofBCBM will be safe and effective. Additionally, in vivomodeling of GABA metabolism in BCBMs is needed tofurther establish this adaptive response in the context ofa full organism. Ultimately, the work presented byNeman and colleagues places us one step closer to suc-cessful therapeutic strategies targeting not only breastcancer cells themselves, but also the supporting brainmicroenvironment, with the goal of improving survivalfor patients with BCBM.AbbreviationsBCBM: Breast cancer brain metastasis; GABA: γ-aminobutyric acid.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsAll authors contributed to the writing and editing of this manuscript.AcknowledgementsThe authors thank our funding sources, including the NCI/NIH (K23157728 toCKA), the Damon Runyon Cancer Research Foundation (Clinical Investigatoraward CI-64-12 to CKA), and the NCI/NIH Cancer Cell Biology Training Grant(2-T32-CA071341-16 to MBS). These supporters have not contributed to thewriting or submission of this manuscript.Author details1Lineberger Comprehensive Cancer Center, University of North Carolina atChapel Hill, 450 West Drive, Campus Box #7295, Chapel Hill, NC 27599, USA.2Department of Genetics, University of North Carolina at Chapel Hill, 120Mason Farm Road, Campus Box #7264, Chapel Hill, NC 27599, USA.3Department of Medicine, Division of Hematology/Oncology, University ofNorth Carolina at Chapel Hill, 170 Manning Drive, POB Room 3119, CampusBox #7305, Chapel Hill, NC 27599, USA.Published:References1. Niwinska A, Murawska M, Pogoda K: Breast cancer brain metastases:differences in survival depending on biological subtype, RPA RTOGprognostic class and systemic treatment after whole-brain radiotherapy(WBRT). Ann Oncol 2010, 21:942–948.2. Ewend MG, Morris DE, Carey LA, Ladha AM, Brem S: Guidelines for theinitial management of metastatic brain tumors: role of surgery,radiosurgery, and radiation therapy. J Natl Compr Canc Netw 2008,6:505–513. quiz 514.3. Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, Anders C, Ewend M, Perou CM:Genomic analysis identifies unique signatures predictive of brain, lung,and liver relapse. Breast Cancer Res Treat 2012, 132:523–535.4. Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, Foekens JA, MartensJW: Subtypes of breast cancer show preferential site of relapse. CancerRes 2008, 68:3108–3114.5. Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, Chaft JE, Kris MG,Huse JT, Brogi E, Massagué J: Serpins promote cancer cell survival andvascular co-option in brain metastasis. Cell 2014, 156:1002–1016.6. Wang L, Cossette SM, Rarick KR, Gershan J, Dwinell MB, Harder DR,Ramchandran R: Astrocytes directly influence tumor cell invasion andmetastasis in vivo. PLoS One 2013, 8:e80933.7. Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D,Barillé-Nion S, Georgakoudi I, Dagg A, McDermott EW, Duffy MJ, McGowanPM, Schlomann U, Parsons M, Bartsch JW, Sonenshein GE: ADAM806 May 2014Van Swearingen et al. Breast Cancer Research Page 3 of 32014, 16:304http://breast-cancer-research.com/content/16/3/304expression in invasive breast cancer promotes tumor dissemination andmetastasis. EMBO Mol Med 2014, 6:278–294.8. Malin D, Strekalova E, Petrovic V, Deal AM, Al Ahmad A, Adamo B, Miller CR,Ugolkov A, Livasy C, Fritchie K, Hamilton E, Blackwell K, Geradts J, Ewend M,Carey L, Shusta EV, Anders CK, Cryns VL: AlphaB-Crystallin: a novelregulator of breast cancer metastasis to the brain. Clin Cancer Res 2014,20:56–67.9. Kim SJ, Kim JS, Park ES, Lee JS, Lin Q, Langley RR, Maya M, He J, Kim SW,Weihua Z, Balasubramanian K, Fan D, Mills GB, Hung MC, Fidler IJ:Astrocytes upregulate survival genes in tumor cells and induceprotection from chemotherapy. Neoplasia 2011, 13:286–298.10. Xing F, Kobayashi A, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, WilberA, Mo YY, Moore BE, Liu W, Fukuda K, Iiizumi M, Sharma S, Liu Y, Wu K,Peralta E, Watabe K: Reactive astrocytes promote the metastatic growthof breast cancer stem-like cells by activating Notch signalling in brain.EMBO Mol Med 2013, 5:384–396.11. Neman J, Choy C, Kowolik CM, Anderson A, Duenas VJ, Waliany S, Chen BT,Chen MY, Jandial R: Co-evolution of breast-to-brain metastasis and neuralprogenitor cells. Clin Exp Metastasis 2013, 30:753–768.12. Fitzgerald DP, Palmieri D, Hua E, Hargrave E, Herring JM, Qian Y, Vega-ValleE, Weil RJ, Stark AM, Vortmeyer AO, Steeg PS: Reactive glia are recruited byhighly proliferative brain metastases of breast cancer and promotetumor cell colonization. Clin Exp Metastasis 2008, 25:799–810.13. Gril B, Palmieri D, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, Andreu Z,Masana D, Fernández P, Steeg PS, Vidal-Vanaclocha F: Pazopanib inhibitsthe activation of PDGFRbeta-expressing astrocytes in the brain metastaticmicroenvironment of breast cancer cells. Am J Pathol 2013, 182:2368–2379.14. Gril B, Palmieri D, Qian Y, Smart D, Ileva L, Liewehr DJ, Steinberg SM, SteegPS: Pazopanib reveals a role for tumor cell B-Raf in the prevention ofHER2+ breast cancer brain metastasis. Clin Cancer Res 2011, 17:142–153.15. Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM, Li H,Hambrecht AC, Roberts E, Jandial R: Human breast cancer metastases tothe brain display GABAergic properties in the neural niche. Proc NatlAcad Sci U S A 2014, 111:984–989.16. Park ES, Kim SJ, Kim SW, Yoon SL, Leem SH, Kim SB, Kim SM, Park YY,Cheong JH, Woo HG, Mills GB, Fidler IJ, Lee JS: Cross-species hybridizationof microarrays for studying tumor transcriptome of brain metastasis.Proc Natl Acad Sci U S A 2011, 108:17456–17461.17. Paget S: The distribution of secondary growths in cancer of the breast.1889. Cancer Metastasis Rev 1989, 8:98–101.18. Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’hypothesis revisited. Nat Rev Cancer 2003, 3:453–458.19. Warburg O: On the origin of cancer cells. Science 1956, 123:309–314.20. Madsen KK, Larsson OM, Schousboe A: Regulation of excitation by GABAneurotransmission: focus on metabolism and transport. Results Probl CellDiffer 2008, 44:201–221.Cite this article as: Van Swearingen et al.: Breast cancer brainmetastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’transition? Breast Cancer Research10.1186/bcr36512014, 16:304

Van Swearingen et al. Breast Cancer Research 2014, 16:304
http://breast-cancer-research.com/content/16/3/304VIEWPOINTBreast cancer brain metastases: evidence for
neuronal-like adaptation in a ‘breast-to-brain’
transition?
Amanda ED Van Swearingen1, Marni B Siegel1,2 and Carey K Anders1,3*Abstract
Brain metastases remain a significant challenge in the
treatment of breast cancer patients due to the unique
environment posed by the central nervous system. A
better understanding of the biology of breast cancer
cells that have metastasized to the brain is required to
develop improved therapies. A recent Proceedings of
the National Academy of Sciences article demonstrates
that breast cancer cells in the brain microenvironment
express γ-aminobutyric acid (GABA)-related genes,
enabling them to utilize GABA as an oncometabolite,
thus gaining a proliferative advantage. In this viewpoint,
we highlight these findings and their potential impact
on the treatment of breast cancer brain metastases.metastatic primary breast cancer cells already express
proteins that are essential for the establishment of brainBreast cancer brain metastases represent a
clinically unmet need and are poorly understood
Breast cancer brain metastases (BCBMs) are an increa-
singly common occurrence and portend a poor progno-
sis [1]. Treatment of BCBMs represents an unmet
medical need as there are currently no approved thera-
pies aside from surgical resection and cranial radiation
[2]. Limited systemic treatment options for BCBMs are
due, in part, to the unique challenges posed by the
neural environment. Protection afforded by the blood-
brain barrier produces an immune-privileged sanctuary
and prevents many systemic therapies from penetrating
the brain, affording cancer cells unique opportunities to
flourish within the neural environment. The added com-
plication of drug delivery to BCBMs coupled with our* Correspondence: carey_anders@med.unc.edu
1Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, 450 West Drive, Campus Box #7295, Chapel Hill, NC 27599, USA
3Department of Medicine, Division of Hematology/Oncology, University of
North Carolina at Chapel Hill, 170 Manning Drive, POB Room 3119, Campus
Box #7305, Chapel Hill, NC 27599, USA
Full list of author information is available at the end of the article
© Van Swearingen et al.; license BioMed Ce
6 months following its publication. After this time
(http://creativecommons.org/licenses/by/4.0), whi
the original work is properly credited. The Creativ
publicdomain/zero/1.0/) applies to the data mad
2014poor understanding of the factors unique to BCBM
growth, metabolism, and stromal interactions continues
to hinder the development of effective therapeutic
strategies.
Two major questions regarding BCBMs are (1) what
factors optimize BCBM cells to seed and survive in the
brain microenvironment, and (2) whether the factors are
present in the primary breast cancer cells or are ac-
quired during metastasis. Among the breast cancer sub-
types, HER2-enriched (HER2+) and triple-negative
primary tumors show higher rates of brain relapse rela-
tive to hormone receptor-positive tumors [3,4], suggest-
ing that some innate feature(s) of primary tumor cells
may dictate the development of brain metastases. Recent
literature suggests that, prior to reaching the brain, some
metastases, including serpins [5], matrix metallopro-
teases [6,7], and αB-crystallin [8]. Once in the brain, re-
cent studies have shown BCBM cells transform the
surrounding glia and neurons to create a more permis-
sive microenvironment [9-11]. Of note, tumor-activated
astrocytes have been shown to play a chemo-protective
role for brain metastases [9] and enhance cancer cell
proliferation and survival [6,12]. Targeting reactive astro-
cytes in the tumor microenvironment yields therapeutic
benefit in vivo by decreasing cancer cell seeding growth
in the brain [13,14]. Thus, current evidence suggests that
BCBMs are the result of both primed breast cancer cells
as well as adaptation to and alteration of the brain-
tumor microenvironment. Better understanding of the
brain microenvironment and its interactions with breast
cancer cells are critical for the development of improved
treatments for BCBMs.ntral Ltd. The licensee has exclusive rights to distribute this article, in any medium, for
, the article is available under the terms of the Creative Commons Attribution License
ch permits unrestricted use, distribution, and reproduction in any medium, provided
e Commons Public Domain Dedication waiver (http://creativecommons.org/
e available in this article, unless otherwise stated.
Van Swearingen et al. Breast Cancer Research Page 2 of 32014, 16:304
http://breast-cancer-research.com/content/16/3/304New research provides evidence for breast cancer
metabolic adaptation to the unique brain
microenvironment
A recent elegant study by Neman and colleagues [15] in-
vestigated whether human BCBMs develop from primed
cells in the primary tumor, or if surviving metastatic
cells adapt to the brain’s unique microenvironment.
The authors compare triple-negative and HER2+ primary
breast tumors, brain metastases, and representative
human-derived cell lines. Relative to both primary tumors
and cell lines, the brain metastases exhibit increased
expression of several components related to signaling
of the inhibitory neurotransmitter γ-aminobutyric acid
(GABA), including GABAA receptors, GABA transporters
(vesicular GABA transporter, GABA transporter 1-3,
GABA-betaine transporter, and glutamate decarboxylase),
and GABA transaminase. The study demonstrates that
upregulation of GABA-related proteins enables increased
transport and metabolism of GABA in BCBMs cells,
thereby increasing cell proliferation. The BCBMs cells also
acquire features of GABAergic interneurons, expressing
interneuron-specific markers like parvalbumin and reelin,
characteristics not seen in the primary tumors.
Future treatments should target the permissive
brain microenvironment and the resulting
adaptations in addition to breast cancer cells
themselves
This work represents one of the few studies that directly
compares human primary breast tumors with brain me-
tastases (rather than assessing brain metastases alone
and/or breast cancer cell lines in vitro or in mouse
models) to identify novel factors involved in BCBM bio-
logy. These results also add to a growing body of evi-
dence showing a ‘breast-to-brain’ transition with cancer
cells adapting to the unique brain microenvironment
and acquiring neuronal characteristics that are not seen
at either the primary and/or other non-brain metastatic
sites [16]. The possibility remains, however, that a small
population of ‘seed’ cells in primary tumors are primed
for brain metastases with additional adaptations that
occur in the brain microenvironment ‘soil’ [17,18].
The acquisition of a novel, neuronal-like GABA shunt
metabolism by the BCBM cells is one of the most
groundbreaking findings of Neman and colleagues’ art-
icle. Cancer cells can exhibit a glycolytic, Warburg-like
metabolism instead of oxidative phosphorylation as seen
in normal tissues [19]; the GABA shunt in BCBMs re-
flects yet another metabolic and proliferative advantage
utilized by breast cancer cells within the neural environ-
ment by providing additional energy through generation
of nicotinamide adenine dinucleotide. This acquired
metabolism may provide a unique target for brain me-
tastases using therapies that inhibit GABA metabolism.Notably, several inhibitors of GABA are approved in the
clinical setting for treatment of epilepsy [20]; however,
careful research is required to determine whether selec-
tively targeting this oncometabolite in the setting of
BCBM will be safe and effective. Additionally, in vivo
modeling of GABA metabolism in BCBMs is needed to
further establish this adaptive response in the context of
a full organism. Ultimately, the work presented by
Neman and colleagues places us one step closer to suc-
cessful therapeutic strategies targeting not only breast
cancer cells themselves, but also the supporting brain
microenvironment, with the goal of improving survival
for patients with BCBM.
Abbreviations
BCBM: Breast cancer brain metastasis; GABA: γ-aminobutyric acid.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All authors contributed to the writing and editing of this manuscript.
Acknowledgements
The authors thank our funding sources, including the NCI/NIH (K23157728 to
CKA), the Damon Runyon Cancer Research Foundation (Clinical Investigator
award CI-64-12 to CKA), and the NCI/NIH Cancer Cell Biology Training Grant
(2-T32-CA071341-16 to MBS). These supporters have not contributed to the
writing or submission of this manuscript.
Author details
1Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, 450 West Drive, Campus Box #7295, Chapel Hill, NC 27599, USA.
2Department of Genetics, University of North Carolina at Chapel Hill, 120
Mason Farm Road, Campus Box #7264, Chapel Hill, NC 27599, USA.
3Department of Medicine, Division of Hematology/Oncology, University of
North Carolina at Chapel Hill, 170 Manning Drive, POB Room 3119, Campus
Box #7305, Chapel Hill, NC 27599, USA.
Published:
References
1. Niwinska A, Murawska M, Pogoda K: Breast cancer brain metastases:
differences in survival depending on biological subtype, RPA RTOG
prognostic class and systemic treatment after whole-brain radiotherapy
(WBRT). Ann Oncol 2010, 21:942–948.
2. Ewend MG, Morris DE, Carey LA, Ladha AM, Brem S: Guidelines for the
initial management of metastatic brain tumors: role of surgery,
radiosurgery, and radiation therapy. J Natl Compr Canc Netw 2008,
6:505–513. quiz 514.
3. Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, Anders C, Ewend M, Perou CM:
Genomic analysis identifies unique signatures predictive of brain, lung,
and liver relapse. Breast Cancer Res Treat 2012, 132:523–535.
4. Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, Foekens JA, Martens
JW: Subtypes of breast cancer show preferential site of relapse. Cancer
Res 2008, 68:3108–3114.
5. Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, Chaft JE, Kris MG,
Huse JT, Brogi E, Massagué J: Serpins promote cancer cell survival and
vascular co-option in brain metastasis. Cell 2014, 156:1002–1016.
6. Wang L, Cossette SM, Rarick KR, Gershan J, Dwinell MB, Harder DR,
Ramchandran R: Astrocytes directly influence tumor cell invasion and
metastasis in vivo. PLoS One 2013, 8:e80933.
7. Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D,
Barillé-Nion S, Georgakoudi I, Dagg A, McDermott EW, Duffy MJ, McGowan
PM, Schlomann U, Parsons M, Bartsch JW, Sonenshein GE: ADAM8
06 May 2014
Van Swearingen et al. Breast Cancer Research Page 3 of 32014, 16:304
http://breast-cancer-research.com/content/16/3/304expression in invasive breast cancer promotes tumor dissemination and
metastasis. EMBO Mol Med 2014, 6:278–294.
8. Malin D, Strekalova E, Petrovic V, Deal AM, Al Ahmad A, Adamo B, Miller CR,
Ugolkov A, Livasy C, Fritchie K, Hamilton E, Blackwell K, Geradts J, Ewend M,
Carey L, Shusta EV, Anders CK, Cryns VL: AlphaB-Crystallin: a novel
regulator of breast cancer metastasis to the brain. Clin Cancer Res 2014,
20:56–67.
9. Kim SJ, Kim JS, Park ES, Lee JS, Lin Q, Langley RR, Maya M, He J, Kim SW,
Weihua Z, Balasubramanian K, Fan D, Mills GB, Hung MC, Fidler IJ:
Astrocytes upregulate survival genes in tumor cells and induce
protection from chemotherapy. Neoplasia 2011, 13:286–298.
10. Xing F, Kobayashi A, Okuda H, Watabe M, Pai SK, Pandey PR, Hirota S, Wilber
A, Mo YY, Moore BE, Liu W, Fukuda K, Iiizumi M, Sharma S, Liu Y, Wu K,
Peralta E, Watabe K: Reactive astrocytes promote the metastatic growth
of breast cancer stem-like cells by activating Notch signalling in brain.
EMBO Mol Med 2013, 5:384–396.
11. Neman J, Choy C, Kowolik CM, Anderson A, Duenas VJ, Waliany S, Chen BT,
Chen MY, Jandial R: Co-evolution of breast-to-brain metastasis and neural
progenitor cells. Clin Exp Metastasis 2013, 30:753–768.
12. Fitzgerald DP, Palmieri D, Hua E, Hargrave E, Herring JM, Qian Y, Vega-Valle
E, Weil RJ, Stark AM, Vortmeyer AO, Steeg PS: Reactive glia are recruited by
highly proliferative brain metastases of breast cancer and promote
tumor cell colonization. Clin Exp Metastasis 2008, 25:799–810.
13. Gril B, Palmieri D, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, Andreu Z,
Masana D, Fernández P, Steeg PS, Vidal-Vanaclocha F: Pazopanib inhibits
the activation of PDGFRbeta-expressing astrocytes in the brain metastatic
microenvironment of breast cancer cells. Am J Pathol 2013, 182:2368–2379.
14. Gril B, Palmieri D, Qian Y, Smart D, Ileva L, Liewehr DJ, Steinberg SM, Steeg
PS: Pazopanib reveals a role for tumor cell B-Raf in the prevention of
HER2+ breast cancer brain metastasis. Clin Cancer Res 2011, 17:142–153.
15. Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM, Li H,
Hambrecht AC, Roberts E, Jandial R: Human breast cancer metastases to
the brain display GABAergic properties in the neural niche. Proc Natl
Acad Sci U S A 2014, 111:984–989.
16. Park ES, Kim SJ, Kim SW, Yoon SL, Leem SH, Kim SB, Kim SM, Park YY,
Cheong JH, Woo HG, Mills GB, Fidler IJ, Lee JS: Cross-species hybridization
of microarrays for studying tumor transcriptome of brain metastasis.
Proc Natl Acad Sci U S A 2011, 108:17456–17461.
17. Paget S: The distribution of secondary growths in cancer of the breast.
1889. Cancer Metastasis Rev 1989, 8:98–101.
18. Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’
hypothesis revisited. Nat Rev Cancer 2003, 3:453–458.
19. Warburg O: On the origin of cancer cells. Science 1956, 123:309–314.
20. Madsen KK, Larsson OM, Schousboe A: Regulation of excitation by GABA
neurotransmission: focus on metabolism and transport. Results Probl Cell
Differ 2008, 44:201–221.
Cite this article as: Van Swearingen et al.: Breast cancer brain
metastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’
transition? Breast Cancer Research
10.1186/bcr3651
2014, 16:304


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Breast cancer brain metastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’ transition?

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