Development of new biomarkers and therapeutic targets for breast cancer
Prosjekt
- Prosjektnummer
- 2016052
- Ansvarlig person
- Yang Jin
- Institusjon
- Oslo universitetssykehus HF
- Prosjektkategori
- Forskerstipend
- Helsekategori
- Cancer
- Forskningsaktivitet
- 1. Underpinning
Rapporter
Background and objectives:
Although remarkable improvements in prognosis and treatment have been made for breast cancer (BCa) in the last decade, overtreatment, treatment resistance and lack of curative treatments remain problematic. Our study aimed to develop new biomarkers for prognosis and treatment of BCa. We had earlier found that expression of two genes that were originally cloned in our laboratory for their possible roles in prostate cancer (PCa), Six Transmembrane Protein of Prostate 1 and 2 (STAMP1 and STAMP2), were significantly downregulated during BCa progression. Our earlier investigations suggested that STAMPs might play a pivotal role in the pathobiology of BCa and might have utility as biomarkers. In this project, we aimed to assess (1) whether STAMP1 is a potential regulator of ER signaling with implications for endocrine resistance, and (2) how STAMP2 functions to limit the activity of central oncogenic signaling pathways in BCa.
Main results:
In earlier part of this project, we have found that loss of STAMP1 increased the proliferation of T47D BCa cells and activated ERα signalling. During the course of this project we found that STAMP1 interferes with G-protein coupled receptor (GPCR)-mediated signal transduction thereby modulating ER phosphorylation and activation (unpublished data). Specifically, we found that depletion of STAMP1 with small interfering RNAs (siRNAs) potently sensitized the response of prostaglandin E2 (PGE2) receptors to ligand stimulation, thereby not only promoting the proliferation but also enhancing the invasion of BCa cells. The effect of STAMP1 on BCa cell growth was also examined in vivo using xenograft mouse model. In contrast to our in vitro data, depletion of STAMP1 in BCa cells in xenografts in nude mice resulted in slower tumor growth rate compared with the control, indicating an environment dependent effect of STAMP1 on BCa cells. The molecular mechanisms underlying these contradicting findings remains unclear.
In addition to the functional and mechanistic data, we also sought to assess whether the expression level of STAMP1 correlates with patho-biological features of ER+ BCa. To that end, BCa tissue microarrays (TMAs) from 3 independent institutions were analysed for STAMP1 expression by immunohistochemistry. The results suggested that STAMP1 expression is significantly and positively associated with endocrine treatment resistance of ER+ BCa patients.
We also investigated the role of STAMP2 in HER2-positive breast cancer in the last part of the project. Our recent data showed that STAMP2 not only interferes with EGFR-mediated survival, but also suppresses the metastatic potential of BCa cells. We have performed global transcriptomics analysis of STAMP2 knockdown cells and revealed the potential mechanisms of the functions of STAMP2. The data suggest that alterations in iron metabolism and hypoxia response might be the underlying mechanism, which requires further investigation.
Conclusions:
First, we have assessed potential function of STAMP1 in ER+ BCa cells both in vitro and in vivo, as well as the association of STAMP1 expression with disease progression, and our data indicated a context-dependent role of STAMP1 in the pathogenesis of BCa, including a role in treatment resistance. Second, we have explored the biological functions of STAMP2 in BCa and, at least in part, revealed the underlying molecular mechanism. Taken together, our data have provided significant new information on the functional roles of STAMP1 and STAMP2 in BCa, and suggested that both molecules have potential utility in BCa prognosis and treatment. Two papers are in preparation on our findings from the project to be submitted in the coming months. In addition, we have published a review article during the course of the project (Trends in Cancer in 2020 (DOI: 10.1016/j.trecan.2019.12.001)).
As the most widely diagnosed and leading cause of cancer death in women, breast cancer has an enormous toll on society in terms of lives lost as well as economic burden from both loss of productivity as well as significant healthcare costs. More than 70% of breast tumors at diagnosis express ERα (here onwards termed ER), and thus ER-targeted endocrine therapy is the mainstay of current treatment for majority of breast cancer patients. Remarkable improvements in prognosis and treatment of ER+ breast cancer have been made in the last two decades, but endocrine therapy resistance remains a significant challenge in the clinic. Currently, few biomarkers exist to partially predict response/resistance to endocrine therapy and there is a paucity of potential therapeutic targets.
This project aimed to develop novel biomarkers using the STAMP family genes that may have prognostic/predictive information for breast cancer, as well as to understand the underlying mechanisms. The results from the project have provided a good basis for a novel treatment strategy for endocrine resistance through inhibition of STAMP1 expression, which has a major impact once translated into the clinic. Knowledge from this study will help to improve the efficacy of treatment and thus improve health span of breast cancer patients, therefor will have a positive impact on patient care.
NO
Breast cancer (BCa) is the most commonly diagnosed cancer in women globally. Although remarkable improvements in prognosis and treatment have been made in the last decade, overtreatment, treatment resistance and lack of curative treatments remain problematic. Our study aimed to develop new biomarkers for prognosis and treatment of BCa.We have found that expression of two genes that were originally cloned in our laboratory for their possible roles in prostate cancer (PCa), Six Transmembrane Protein of Prostate 1 and 2 (STAMP1 and STAMP2), are significantly downregulated during BCa progression. Our earlier investigation showed that there was significant inverse correlation between STAMPs expression and multiple clinical/pathological parameters of BCa including prognosis. These findings indicated that STAMPs play a pivotal role in pathobiology of BCa and may have utility as biomarkers. We aimed to assess whether STAMP1 is a potential regulator of ER signaling with implication in endocrine resistance, and how STAMP2 functions to limit the activity of central oncogenic signaling pathways in BCa. Our relevant results obtained in year 2020 so far are summarized as follows.
In earlier study of this project we have found that loss of STAMP1 increased the proliferation of BCa cells T47D and activated Estrogen receptor (ER) signaling. Our recent data revealed that STAMP1 interferes with G-protein coupled receptor (GPCR)-mediated signaling transduction thereby modulates ER phosphorylation and activation. We found that depletion of STAMP1 potently sensitized the response of prostaglandin E2 (PGE2) receptors to ligands stimulation. We are finalising the mechanism study and expect to publish these results in 2021.
The role of STAMP2 in HER2-positive breast cancer cells was also investigated in the past project year. Our recent data showed that STAMP2 not only interferes with EGFR-mediated survival of BCa cells, but also suppresses the metastatic potential of BCa cells. We have done transcriptomic analysis of STAMP2 knockdown cells and revealed the potential mechanisms of the functions of STAMP2. Alteration in iron metabolism and hypoxia response might be the underlying mechanisms, of which confirmation us undergoing. We expect to publish these data within one year.
In summary, according the research plan, we have assessed the function of STAMP1 in ER+ BCa cells both in vitro and in vivo, as well as revealed the role of STAMP2 in HER2+ breast cancer cells. Two relevant manuscripts are under preparation and one related review article has been published in the Trends in Cancer.
NO
Breast cancer (BCa) is the second most frequently diagnosed cancer worldwide. Although remarkable improvements in prognosis and treatment have been made in the last decade, overtreatment, treatment resistance and lack of curative treatments remain problematic. Our study aimed to develop new biomarkers for prognosis and treatment of BCa.We have found that expression of two genes that were originally cloned in our laboratory for their possible roles in prostate cancer (PCa), Six Transmembrane Protein of Prostate 1 and 2 (STAMP1 and STAMP2), are significantly downregulated during BCa progression. Our earlier investigation showed that there was significant inverse correlation between STAMPs expression and multiple clinical/pathological parameters of BCa including prognosis. These findings indicated that STAMPs play a pivotal role in pathobiology of BCa and may have utility as biomarkers. We aimed to assess whether STAMP1 is a potential regulator of ER signaling with implication in endocrine resistance, and how STAMP2 functions to limit the activity of central oncogenic signaling pathways in BCa. Our relevant results obtained so far are summarized as follows.
We have first assessed the in vitro and in vivo functions of STAMP1 and STAMP2 in BCa cell growth, survival, invasion and their possible effects on oncogenic signaling pathways in BCa cells. Our results showed that loss of STAMP1 resulted in growth advantage of ER+ BCa cells in vitro, partially through activation of multiple oncogenic signaling pathway, including PI3K-AKT and ERα pathways. The prognostic utility of STAMP1 expression have been evaluated in multiple BCa cohorts and the results suggested that the mRNA expression profile of STAMP1, but not the protein level, significantly predicts the disease progression and survival of ER+ BCa patients. In addition, we also found that STAMP1 implicates in the development of endocrine resistance of ER+ BCa. However, the exact function and molecular mechanism remain unexplored. Unlike STAMP1, STAMP2 is more functional relevant to the ER negative (ER-) BCa, including both the HER2 positive and the triple negative BCa (TNBC) subtypes. Our current data showed that STAMP2 not only interferes with EGFR-mediated survival of BCa cells, but also suppresses the metastatic potential of BCa cells. The detailed mechanism and potential utility of STAMP2 in BCa prognosis are under investigation.
In summary, according the research plan, we have conclusively assessed the function of STAMP1 in ER+ BCa cells both in vitro and in vivo, as well as the association of STAMP1 expression with disease progression. In addition, we have explored the biological functions of STAMPs in BCa and partially revealed the underlying molecular mechanism. To conclude, our data have delineated, although not fully, the functional roles of STAMP1 and STAMP2 in BCa, and suggested that both molecules have potential utility in BCa prognosis and treatment.
NO
Vi har utført funksjonell analyse av STAMP proteinene i brystkreft celler og den relevante molekylære mekanismen har blitt belyst i løpet av det siste årets forskning.Våre tidligere studier har vist at medlemmer av protein familien Six Transmembrane Protein of Prostate (STAMP), STAMP1 and STAMP2, er dysregulert under brystkreft progresjon og er signifikant relatert til flere klinisk patologiske parametere i brystkreft klassifisering og prognose. Vår hypotese er at disse to genene er sentrale i brystkreft patobiologi og at de har nytte som biomarkører for brystkreft diagnostisering og målrettede terapier. Hovedmålet med dette prosjektet er å teste denne hypotesen og vurdere nytten av disse to genene som prognostiske markører som kan benyttes i klinikken.
Vi har evaluert STAMP1 protein uttrykk i flere brystkreft kohorter fra våre samarbeidspartnere i Norge og Finland. Sammenhengen mellom STAMP1 og ulike klinisk patologiske karakteristikker, inkludert sykdomsstadier, endokrin resistens og overlevelse undergår nå statistisk analyse. Valideringen av den kliniske relevansen for STAMP2 for brystkreft er også godt på vei. Når det gjelder de biologiske funksjonene til STAMP1 og STAMP2 i brystkreft celler og eksperimentelle undersøkelser, inkludert ulike cellulære analyser og tumor vekst analyser i en dyremodell, har disse blitt fullført som planlagt. Mekanistisk, har vi undersøkt den molekylære virkningsmekanismen av STAMP1 i østrogen reseptor positive brystkreft celler ved transkriptomisk analyse og undersøkelser av onkogene signalveier. Lignende analyser ble utført for å utforske den funksjonelle mekanismen til STAMP2 i trippel-negative brystkreft celler.
Våre eksperimentelle undersøkelser til nå har vist at brystkreft celler med sterkt redusert STAMP1 nivå fikk signifikante vekst fordeler og at dysreguleringen er assosiert med utviklingen av endokrin resistens. Vi har også funnet at utrykket av STAMP2 har hemmende funksjon på trippel-negativ brystkreft celle vekst og invasjon. Nå er mekanismen for sammenhengen mellom STAMP1 og brystkreft blitt oppdaget og en relevant vitenskapelig rapport er underveis. Imidlertid har utviklingen av en klinisk nyttig prognostisk multi-gen biomarkør basert på nåværende resultater blitt gjennomført som planlagt og skal nå videre optimaliseres og valideres.
NO
Brystkreft er den mest vanlige kreftformen hos kvinner i den vestlige verden. Nylig utviklede målrettede terapier, slik som interferens med østrogen aktivitet, har betydelig forbedret overlevelse hos pasienter. Men et stort antall pasienter responderer ikke til eller utvikler etter hvert resistens mot disse målrettede terapiene.Brystkreft er den nest mest diagnostiserte krefttypen på verdensbasis. Selv om bemerkelsesverdige fremskritt innen prognose og behandling har blitt gjort i løpet av det siste tiåret, skaper endokrin terapi resistens hos pasienter med østrogenreseptor positiv brystkreft og kjemoterapi resistens ved fremskreden sykdom fortsatt store problemer. Det er et akutt behov for nye terapeutiske mål i tillegg til biomarkører som kan forutsi sykdoms progresjon og respons til målrettet terapi. Ytterligere kunnskap er nødvendig for å forstå grunnlaget for denne resistensen, forbedre prognosen, og i tillegg utvikle nye terapier.
Hovedmålet med dette prosjektet er å videre utforske nye prognostiske biomarkører for brystkreft og belyse hvordan de fungerer i brystkreft progresjon. Tidligere har vi funnet at to medlemmer av en seks transmembran protein familie er deregulert i brystkreft. Disse observasjonene har blitt validert i flere brystkreft kohort ved bruk av gen uttrykk analyse og immunhistokjemi analyse. I eksperimenter med celle modeller, oppdaget vi at funksjonene til disse to genene spiller viktige roller i progresjon av brystkreft og utviklingen av resistens. Våre nåværende bevis for mekanistisk analyse indikerer at en av disse genene er en ny tumor-suppressor for østrogenreseptor positiv brystkreft gjennom interaksjon med flere signalveier. En artikkel basert på disse resultatene er under arbeid og vil bli sendt inn i 2018. Funksjonell karakterisering og klinisk assosiasjon analyser av det andre genet arbeides med som planlagt.
Brystkreft er den mest vanlige kreftformen hos kvinner i den vestlige verden. Nylig utviklede målrettede terapier, slik som interferens med østrogen aktivitet, har betydelig forbedret overlevelse hos pasienter. Men et stort antall pasienter responderer ikke til eller utvikler etter hvert resistens mot disse målrettede terapiene.Brystkreft er den andre mest vanlige diagnostiserte kreftformen i verden. Selv om viktige forbedringer innen prognose og behandling har blitt gjort det siste tiåret, skaper endokrin resistens i ER positiv brystkreft og kjemoterapi resistens i avansert sykdom fortsatt store problemer. Det er derfor et umiddelbart behov for nye terapeutiske mål i tillegg til biomarkører som kan forutsi sykdomsprogresjon og respons til målrettede terapier. Ytterligere kunnskap er nødvendig for å forstå bakgrunnen til denne resistensen, bedre prognose, og utviklingen av nye terapier. Vi har nylig identifisert en gensignatur sentrert rundt to gener som suksessfullt kan forutsi kliniske utfall hos brystkreft pasienter. Konsekvent, i eksperimenter med kultiverte brystkreft celler, fører blokkering av uttrykket til disse genene til aggressiv vekst av brystkreft tumor celler in vitro så vel som i musemodeller av brystkreft.
Hovedmålet med dette prosjektet er å ytterligere undersøke den potensielle bruken av denne gensignaturen som en prognostisk biomarkør og belyse hvordan de fungerer for å hindre brystkreft progresjon. Basert på våre nåværende data har vi nå designet en forbedret multipleks gensignatur som potensielt kan hjelpe til med å gruppere brystkreft pasienter for tilgjengelige behandlings muligheter. Denne nye gensignaturen har vist lik eller bedre prognostisk effekt sammenlignet med gensignaturer som brukes i klinikken i dag. Optimalisering og videre validering av denne gensignaturen i ytterligere brystkreft kohorter er pågående. Vi har også undersøkt de biologiske funksjonene til noen av disse genene i brystkreft celler og identifisert signalveien som blir påvirket for å hindre vekst av brystkreft celler. Det første manuskriptet basert på våre nåværende funn forventes innsendt for publisering i 2017.
Vitenskapelige artikler
Jin Y, Saatcioglu F
Targeting the Unfolded Protein Response in Hormone-Regulated Cancers.
Trends Cancer 2020 02;6(2):160-171. Epub 2020 jan 16
PMID: 32061305
Deltagere
- Assia Vassileva Bassarova Prosjektdeltaker
- Veronica Fitzpatrick Blihovde Doktorgradsstipendiat (annen finansiering)
- Fahri Saatcioglu Medveileder
- Yang Jin Prosjektleder
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
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