Matthew Beatty Brynn Cullander Melissa Frank Justin Ludwig Mosharaf Mahmud Syed Andrew Pierce and Ashton Sigler History Discovered in the 1984 by Roel Nusse and Harold Varmus as the int1 gene ID: 755111
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Slide1
WNT5A and Breast Cancer
Group 1:
Matthew Beatty, Brynn Cullander, Melissa Frank, Justin Ludwig, Mosharaf Mahmud Syed, Andrew Pierce, and Ashton SiglerSlide2
History
Discovered in the 1984 by Roel Nusse and Harold Varmus as the int1 gene.
Later determined to be homologous to the Wg (wingless) gene in
Drosophila.19 ligands in mammals, Wnt3a was the first to be biochemically characterizedTwo major identified pathways: Canonical and Non-Canonical
Kerekes, 2015; Komiya, 2008; Nusse, 2005Slide3
Pathway
Wnt5a is highly conserved
Regulates cell migration, polarity, cell fate, and senescence
Wnts are secreted glycoproteinsA total of 19 in humansThey bind the Frizzled (Fz) receptor family (10 total)
Here signal branches into 3 major pathways:Canonical/β-Catenin DependentPlanar cell polarity--PCP (non-canonical)
Wnt/Ca2+ (non-canonical)
Komiya, 2008Slide4
Canonical Pathway
Canonical β-Catenin-Dependent Pathway
In absence of Wnt, β-Catenin is targeted for ubiquitination by sequential phosphorylation via CK1 and GSK3.
Wnt binds to Frizzled receptor (Fz) and co-receptor. Dishevelled is recruited, and the coreceptor is phosphorylated. β-Catenin phosphorylation is inhibited and it accumulates.
Komiya, 2008Slide5
Non-canonical Pathway
Fig 1: PCP transduction cascade
Wnt binds Fz, Dsh activated
Dsh activates Daam1 which in turn activates Prolifin and Rho, resulting in actin polymerization and changes in cytoskeleton during gastrulationFig 2: Wnt/Ca2+ cascadeWnt binds, Dsh activated via G protein activation
Dsh activates PDE, that inhibits PKG and prevents Ca2+ releaseDsh can also activate PLC which activates IP3 to cause Ca2+ release which has regulatory effects on ventral fate and or tissue separation while inhibiting the canonical pathway
Pathway can also mediate tissue separation and dorsal axis formation
Komiya, 2008Slide6
WNT5A
directs branching
and terminal end bud proliferation (
ductal elongation) in the breast.Two isoformsWNT5A-S (oncogene), WNT5A-L (tumor suppressor)Tumor suppressor form seems to predominate over oncogenic form in breast tissueRegulates terminal end bud proliferationWNT5A localized in mammary luminal cells
Acts in a paracrine fashion on basal tumor initiating cells, inhibiting growth & tumorsFigure right shows effects of WNT5A knockout
Function in Breast
Asem et al., 2016; Roarty, K., & Rosen, J. M., 2010; Zeng et al., 2016
Roarty, K. & Serra, R., 2007Slide7
Function in Breast
Hines, W.C., 2018
https://openi.nlm.nih.gov/imgs/512/48/1413974/PMC1413974_bcr1368-2.png
WNT5A is localized to the luminal cells of the breast terminal end bud.Slide8
Does Wnt5a Suppress or Cause Cancer?
Down Regulation and Over Expression
Wnt5a mRNA levels decrease in cancerous tissue
Heterozygous loss of Wnt5a connected to shorter survival in breast cancer patientsDown regulation of Wnt5a leads to reduction in cell-cell adhesion resulting in metastasis
Up regulation can possibly play a role in abnormal differentiation
May also potentially be a reaction to inhibit cell differentiation
Normal Wnt5a Function
Wnt5a is expressed at low levels in normal breast tissue
Plays role in inhibiting cell transformation
Loss of expression leads to cell transformationSlide9
Why should we care about Wnt-5a and Wnt Pathway Clinically?
-
Abnormal
Wnt-5a expression: various cancers, fibrosis, and inflammation-Isotypes: Wnt5a-L
inhibits and Wnt5a-S increases proliferation
- The exact role played by Wnt5a in cancer remains controversial (both tumor-suppressing and oncogenic effects in different cancer types)
-
Functions of Wnt-5a: drastically altered depending on the availability of key receptors
-
Additional studies: determine the mechanism by which isoform expression contributes to oncogenesis
-Wnt-5a used as therapeutic target
Asem et al, 2016;
Kumawat et al, 2016Slide10
Drug Development and Targeted Therapies for Triple-Negative Breast Cancer
1)
Vantictumab:
Human IgG2 monoclonal Ab
- Frizzled receptors: transmits growth and survival signals to BCSCs
- Vantictumab
binds to the frizzled receptors
-Mutes signals from the Wnt pathway
-TNBC stem cells can’t grow, survive and replicate
- 33% of the 21 patients treated in the trial achieved a partial response (Not approved yet for treatment)
2)
Wnt-5a as a therapeutic target:
a)Foxy-5:
formylated Wnt5a-derived hexapeptide
- Mimics tumor suppressive effects of Wnt-5a molecule on BC
-Foxy-5 reduced metastatic burden in the lungs and liver in BC mouse model (currently in phase 1 and extremely promising)
b)
Box5:
Inhibits
Wnt5a signaling reduces Wnt5a-induced melanoma cell migration
3)
Wnt Signaling inhibitor: CWP232228 (targets BCSC and tumors)
-
Inhibits β-catenin/TCF-mediated transcription in nucleus
-Inhibition of TNBC SC proliferation and reduction of tumor bulk
UC Anschutz Medical Campus, 2016;
Jang et al, 2015; Kumawat et al, 2016; Andersson et al, 2015 Slide11
Current Research
Wnt5a−/− mice exhibit
dwarfism
shortened limbs and tails
lungs with foreshortened trachea
facial, ear, and genital abnormalities
ventricular septal defects.
These mice die shortly after birth
Wnt5a knockout mice show increased β-catenin signaling
Possible Wnt5a/Ror2 pathway that inhibits Wnt/β-catenin signaling
in vivo
.
(Amerongen et al. 2012)
(Ho et. al 2012)Slide12
Current Research
“The role of Wnt5a expression in breast cancer remains elusive.” (Kobayashi et al., 2018)
Estrogen Receptor Positive Breast CA
Increased Wnt5a expression correlated with poor prognosis
Higher incidence of malignancy, cell invasion, and metastases
Wnt5a found to induce ALCAM which induces cell migration
Triple Negative Breast CA
Increased Wnt5a expression correlated with increased survival
Lower incidence of metastases and CA migration
Wnt5a-CKIα signaling axis has been shown to promote β-catenin/E-cadherin complex formation, thus promoting cell adhesion
mRNA isoforms
Wnt5a-S elevated in breast CA (oncogenic?)
Wnt5a-L decreased in breast CA (tumor suppressor?)
(Prasad et al., 2018)
(Kobayashi et al., 2018)Slide13
Current Research
“The role of Wnt5a expression in breast cancer remains elusive.” (Kobayashi et al., 2018)
Problems in research
Expression of Wnt5a protein not always correlated with expression of Wnt5a mRNA due to translational regulation.
Many previous studies found a correlation between Wnt5a and breast CA - but without isolating the effect of Wnt5a on different subtypes of CA
Future Research
Further study of the effect of Wnt5a on isolated subtypes of CA
Elucidate the mechanism of Wnt5a and its downstream effectors on cell migration and adhesion
Further study on the functions of Wnt5a-L and Wnt5a-S and their possible protein isoformsSlide14
Conclusion and Take Homes
History
Pathway
Function in BreastWhether Wnt5a causes or suppresses cancerWhy we should care and how Wnt5a is used clinically
Drug development and target therapiesCurrent ResearchSlide15
Thank You!
Questions?
Slide16
References
University of Colorado Anschutz Medical Campus. (2016, June 4). “Finally, targeted therapies for triple-negative breast cancer: Promising clinical trials of IMMU-132, vantictumab and atezolizumab against TNBC”.
Medical Xpress.
Retrieved 12 October 2018 from https://medicalxpress.com/news/2016-06-therapies-triple-negative-breast-cancer.html
Bauer, M., Bénard, J., Gaasterland, T., Willert, K., & Cappellen, D. (2013).WNT5A Encodes Two Isoforms with Distinct Functions in Cancers.
PLoS ONE, 8
(11), e80526. http://doi.org/10.1371/journal.pone.0080526
Kumawat, K., & Gosens, R. (2016). WNT-5A: signaling and functions in health and disease.
Cellular and Molecular Life Sciences
,
73
, 567–587.
http://doi.org/10.1007/s00018-015-2076-y
Asem, M. S., Buechler, S., Wates, R. B., Miller, D. L., & Stack, M. S. (2016). Wnt5a Signaling in Cancer.
Cancers
,
8
(9), 79.
http://doi.org/10.3390/cancers8090079
Jang, G. B., Hong, I. S., Kim, R. J., Lee, S. Y., Park, S. J., Lee, E. S., ... & Lee, H. Y. (2015). Wnt/β-catenin small molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells.
Cancer research
, canres-2041.
Pohl, S.-G., Brook, N., Agostino, M., Arfuso, F., Kumar, A. P., & Dharmarajan, A. (2017). Wnt signaling in triple-negative breast cancer.
Oncogenesis
,
6
(4), e310–.
http://doi.org/10.1038/oncsis.2017.14
Andersson, T., Axelsson, L., Mohapatra, P., Prasad, C., Soerensen, P. G., Mau-Soerensen, M., ... & Nielsen, D. (2015). Abstract A116: targeting the Wnt-5a signaling pathway as a novel anti-metastatic therapy.
Molecular Targets and Cancer Therapeutics, 14
(12).Slide17
References
Ho, Hsin-Yi Henry, Michael W. Susman, Jay B. Bikoff, Yun Kyoung Ryu, Andrea M. Jonas, Linda Hu, Rejji Kuruvilla, and Michael Eldon Greenberg. “Wnt5a–Ror–Dishevelled Signaling Constitutes a Core Developmental Pathway That Controls Tissue Morphogenesis.”
Proceedings of the National Academy of Sciences
109, no. 11 (March 13, 2012): 4044–51. https://doi.org/10.1073/pnas.1200421109.Kerekes, K., Bányai, L., & Patthy, L. (2015). Wnts grasp the WIF domain of Wnt Inhibitory Factor 1 at two distinct binding sites.
FEBS Letters, 589(20, Part B), 3044–3051. https://doi.org/10.1016/j.febslet.2015.08.031
Kobayashi, Yoshie, Takayuki Kadoya, Ai Amioka, Hideaki Hanaki, Shinsuke Sasada, Norio Masumoto, Hideki Yamamoto, Koji Arihiro, Akira Kikuchi, and Morihito Okada. “Wnt5a-Induced Cell Migration Is Associated with the Aggressiveness of Estrogen Receptor-Positive Breast Cancer.”
Oncotarget
9, no. 30 (April 20, 2018): 20979–92. https://doi.org/10.18632/oncotarget.24761.
Komiya, Y., & Habas, R. (2008). Wnt signal transduction pathways.
Organogenesis
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(2), 68–75.
MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/β-catenin signaling: components, mechanisms, and diseases.
Developmental Cell
,
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(1), 9–26. https://doi.org/10.1016/j.devcel.2009.06.016
Nusse, R. (2005). Wnt signaling in disease and in development.
Cell Research
,
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(1), 28–32. https://doi.org/10.1038/sj.cr.7290260Slide18
References
Prasad, Chandra Prakash, Mansi Manchanda, Purusottam Mohapatra, and Tommy Andersson. “WNT5A as a Therapeutic Target in Breast Cancer.”
Cancer and Metastasis Reviews
, August 31, 2018. https://doi.org/10.1007/s10555-018-9760-y.
Roarty, K., & Rosen, J. M. (2010). Wnt and mammary stem cells: hormones cannot fly wingless. Current opinion in pharmacology, 10(6), 643-649.
Zeng, R., Huang, J., Zhong, M., Li, L., Yang, G., Liu, L., … Wu, Z. (2016). Multiple Roles of WNT5A in Breast Cancer.
Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 22,
5058–5067. http://doi.org/10.12659/MSM.902022.
Roarty, K. & Serra, R. (2007). Wnt5a is required for proper mammary gland development and TGF-β-mediated inhibition of ductal growth.
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(21), 3929-3939.