liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Show others and affiliations
2007 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 12, 3577-3584 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.

Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.

Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.

Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

Place, publisher, year, edition, pages
2007. Vol. 13, no 12, 3577-3584 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-15041DOI: 10.1158/1078-0432.CCR-06-1609PubMedID: 17575221OAI: oai:DiVA.org:liu-15041DiVA: diva2:37726
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-12-11
In thesis
1. Alterations in the PI3K/AKT Signaling Pathway and Response to Adjuvant Treatment in Breast Cancer
Open this publication in new window or tab >>Alterations in the PI3K/AKT Signaling Pathway and Response to Adjuvant Treatment in Breast Cancer
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

(PI3K)/AKT signaling pathway could be a cause of therapeutic resistance in breast cancer. The PI3K/AKT pathway controls cell proliferation, cell growth and survival, and its members include oncogenes and tumor suppressor genes. Alterations in this pathway are frequent in cancer. In this thesis, we aimed to study the biological significance of some of these alterations in a tumor context as well as their clinical value. PIK3CA gene, encoding the PI3K catalytic subunit, was examined for mutations. The tumor suppressor PTEN, that counteracts PI3Kmediated effects, was studied at the protein level whereas amplification of RPS6KB1 (S6K1) and RPS6KB2 (S6K2) genes, encoding two substrates of the mammalian target of rapamycin (mTOR) acting downstream PI3K/AKT, was also inspected. AKT phosphorylation or activation (pAKT) was determined by immunohistochemistry. Other factors related with this pathway, such as HER-2, heregulin (HRG) β1, the cell cycle inhibitor p21WAF1/CIP1, the pro-apoptotic factor Bcl-2, and cyclin D1,  were also considered. These studies were perfomed in two patient materials consisting of premenopausal patients that received endocrine treatment (paper I) and postmenopausal patients randomized to receive radiotherapy (RT) or chemotherapy (CMF) in combination with tamoxifen (Tam) or no endocrine treatment (papers II-IV). In the first material, we found that pAKT indicated higher risk of distant recurrence among endocrine treated patients. In the second material HRGβ1 induced accumulation cytoplasmic p21 in vitro and pAKT was associated with cytoplasmic p21 in the tumors. In addition, p21 cellular location identified subgroups of ER+ patients with different responses to tamoxifen. Other alterations such as PIK3CA mutations and PTEN loss were positively associated in this material. PIK3CA mutations lowered the risk for local recurrences while PTEN loss conferred radiosensitivity as a single variable or combined with mutated PIK3CA. PIK3CA mutations and/or PTEN loss was associated with lower S-phase (SPF). Nevertheless, among patients with low proliferating tumors, these alterations predicted higher risk of recurrence in contrast to those with high proliferating tumors. Finally, we found amplification of the S6K1 and S6K2 genes. S6K2 amplification was associated with cyclin D1 gene amplification, predicted poor recurrence-free survival and breast cancer death, and indicated benefit from tamoxifen. On the other hand, S6K1 amplification was associated with HER-2 amplification/overexpression, indicated higher risk of recurrence and was a predictor of poor response to radiotherapy. These results indicate the potential of this pathway as therapeutic source.

 

Abstract [sv]

Bröstcancer är en vanlig sjukdom och dödsorsak bland kvinnor i Sverige. Könshormonet östrogen tillsammas med cellernas receptorer för hormonet spelar en viktig roll för bröstcancerutvecklingen. Därför behandlas denna sjukdom med anti-hormonella substanser inriktade mot hämning av östrogensyntes/östrogen receptorn. Tamoxifen är den vanligaste formen av anti-östrogenbehandling som används efter operation. Tamoxifenbehandling förbättrar betydligt 5-årsöverlevnaden hos patienter med östrogenreceptorpositiva tumörer. Emellertid finns det patienter som återkommer med metastaser efter en tid. I det här projektet studerar vi andra receptorer samt deras signalvägar som kan aktivera östrogenreceptorn och därmed orsaka tamoxifenresistens.

En sådan receptor är HER-2 vilken överuttrycks i 15-20% vid bröstumörer. HER-2 receptorn kan rekrytera proteiner med enzymatisk aktivitet, till exempel PI3K. PI3K aktiverar ett annat enzym, AKT, vilket är inblandat i en kaskad som leder till tumörtillväxt och tumöröverlevnad (genom till exempel aktivering av östrogenreceptorn). Våra resultat hitills visar att patienter med aktiverat AKT (pAKT) har större risk att få metastaser och därmed sämre överlevnad än patienter utan pAKT, detta trots hormonell behandling. I större material där HER-2 proteinuttrycket korrelerar med pAKT har vi också funnit att patienter med AKTnegativa tumörer kunde dra nytta av både tamoxifen och strålbehandling. Vi har även undersökt PIK3CA genen (som kodar för en del av PI3K) och hittat mutationer i 24% av bröstumörerna. Det är dock ännu oklart hur dessa mutationer ska tas hänsyn till för att kunna bestämma en effektiv behandling. PTEN är ett annat enzym som motverkar PI3K-aktivitet. Bortfall av PTEN förekommer ofta i bröstcancer och  har associerats med PI3K/AKT aktivering. I vårt material var PTEN-förlust frekvent (37%) och associerades med PIK3CA mutationer. PTEN förlust som ensam faktor eller tillsammans med PIK3CA mutationer ökade strålkänslighet. Andra proteiner som är inblandade i PI3K signalvägen är S6K1 och S6K2 och dessa har betydelse för cellens proteinsyntes. Nyligen har vi kunnat visa att generna för både S6K1/2 finns i många kopior (genamplifering) I tumörcellerna hos bröstcancerpatienter. Dessutom fanns det ett positivt samband mellan S6K1/2 amplifiering och amplifiering av andra kända cancergener (som t. ex HER-2 och cyclin D1) men förhållandet till PIK3CA-mutationer var det omvända. Patienter med antigen S6K1 eller HER-2 amplifierade tumörer svarade dåligt på strålbehandling men skulle möjligen kunna behandlas med en specifik substans riktad mot S6K1 eller HER-2. Ett ökat antal kopior av S6K2 indikerade dålig prognos men bra nytta av tamoxifen. Våra resultat visar att PI3K/AKT signalvägen ofta är aktiverad vid bröstcancer och skulle kunna vara en viktig måltavla för behandling.

Place, publisher, year, edition, pages
Link: Linköping University Electronic Press, 2008. 105 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1078
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-15043 (URN)978-91-7393-810-5 (ISBN)
Public defence
2008-10-03, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2009-08-21Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedLink to Ph.D. Thesis

Authority records BETA

Pérez-Tenorio, GizehAlkhori, LizaOlsson, BirgitAhnstro Waltersson, MarieNordenskjöld, BoStål, Olle

Search in DiVA

By author/editor
Pérez-Tenorio, GizehAlkhori, LizaOlsson, BirgitAhnstro Waltersson, MarieNordenskjöld, BoStål, Olle
By organisation
Oncology Faculty of Health SciencesDepartment of Clinical and Experimental MedicineDepartment of Oncology UHL
In the same journal
Clinical Cancer Research
Cancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 164 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf