Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting

Dissertation

Sirkku Pollari

Research output: ThesisDissertationCollection of Articles

Abstract

Breast cancer that has metastasized to bone is currently an incurable disease, causing significant morbidity and mortality. The aim of this thesis work was to elucidate molecular mechanisms of bone metastasis and thereby gain insights into novel therapeutic approaches. First, we found that L-serine biosynthesis genes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) and phosphoserine phosphatase (PSPH), were up-regulated in highly bone metastatic MDA-MB-231(SA) cells as compared with the parental breast cancer cell line. Knockdown of serine biosynthesis inhibited proliferation of MDA-MB-231(SA) cells, and L-serine was essential for the formation of bone resorbing osteoclasts. Clinical data demonstrated that high expression of PHGDH and PSAT1 was associated with decreased relapse-free and overall survival and with features typical of poor outcome in breast cancer. Second, RNA interference screening pointed out heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for transforming growth factor ß (TGF-ß)-induced interleukin 11 (IL-11) production in MDA-MB-231(SA) cells. Exogenous heparan sulfate glycosaminoglycans heparin and K5-NSOS also inhibited TGF-ß-induced IL-11 production in MDA-MB-231(SA) cells. Furthermore, K5-NSOS decreased osteolytic lesion area and tumor burden in bone in mice. Third, we discovered that the microRNAs miR-204, -211 and -379 inhibited IL-11 expression in MDA-MB-231(SA) cells through direct targeting of the IL-11 mRNA. MiR-379 also inhibited Smad-mediated signaling. Gene expression profiling of miR-204 and -379 transfected cells indicated that these microRNAs down-regulate several bone metastasis-relevant genes, including prostaglandin-endoperoxide synthase 2 (PTGS2). Taken together, this study identified three potential treatment strategies for bone metastatic breast cancer: inhibition of serine biosynthesis, heparan sulfate glycosaminoglycans and restoration of miR-204/-211/-379.
Original languageEnglish
QualificationDoctor Degree
Awarding Institution
  • University of Turku
Supervisors/Advisors
  • Kallioniemi, Olli, Supervisor, External person
  • Käkönen, Sanna-Maria, Supervisor, External person
Place of PublicationTurku
Publisher
Print ISBNs978-951-29-4961-8
Electronic ISBNs978-951-29-4962-5
Publication statusPublished - 2012
MoE publication typeG5 Doctoral dissertation (article)

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Bone Neoplasms
Interleukin-11
phosphoserine aminotransferase
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Serine
Phosphoglycerate Dehydrogenase
Heparitin Sulfate
Transforming Growth Factors
Glycosaminoglycans
MicroRNAs
Therapeutics
Genes
Gene Expression Profiling
Osteoclasts
Prostaglandin-Endoperoxide Synthases
RNA Interference
Tumor Burden
Osteogenesis

Keywords

  • breast cancer
  • bone metastasis
  • L-serine
  • IL-11
  • heparan sulfate glycosaminoglycan
  • microRNA
  • rintasyöpä
  • luustoetäpesäke
  • L-seriini
  • hepariinisulfaatti

Cite this

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title = "Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting: Dissertation",
abstract = "Breast cancer that has metastasized to bone is currently an incurable disease, causing significant morbidity and mortality. The aim of this thesis work was to elucidate molecular mechanisms of bone metastasis and thereby gain insights into novel therapeutic approaches. First, we found that L-serine biosynthesis genes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) and phosphoserine phosphatase (PSPH), were up-regulated in highly bone metastatic MDA-MB-231(SA) cells as compared with the parental breast cancer cell line. Knockdown of serine biosynthesis inhibited proliferation of MDA-MB-231(SA) cells, and L-serine was essential for the formation of bone resorbing osteoclasts. Clinical data demonstrated that high expression of PHGDH and PSAT1 was associated with decreased relapse-free and overall survival and with features typical of poor outcome in breast cancer. Second, RNA interference screening pointed out heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for transforming growth factor {\ss} (TGF-{\ss})-induced interleukin 11 (IL-11) production in MDA-MB-231(SA) cells. Exogenous heparan sulfate glycosaminoglycans heparin and K5-NSOS also inhibited TGF-{\ss}-induced IL-11 production in MDA-MB-231(SA) cells. Furthermore, K5-NSOS decreased osteolytic lesion area and tumor burden in bone in mice. Third, we discovered that the microRNAs miR-204, -211 and -379 inhibited IL-11 expression in MDA-MB-231(SA) cells through direct targeting of the IL-11 mRNA. MiR-379 also inhibited Smad-mediated signaling. Gene expression profiling of miR-204 and -379 transfected cells indicated that these microRNAs down-regulate several bone metastasis-relevant genes, including prostaglandin-endoperoxide synthase 2 (PTGS2). Taken together, this study identified three potential treatment strategies for bone metastatic breast cancer: inhibition of serine biosynthesis, heparan sulfate glycosaminoglycans and restoration of miR-204/-211/-379.",
keywords = "breast cancer, bone metastasis, L-serine, IL-11, heparan sulfate glycosaminoglycan, microRNA, rintasy{\"o}p{\"a}, luustoet{\"a}pes{\"a}ke, L-seriini, hepariinisulfaatti",
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Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting : Dissertation. / Pollari, Sirkku.

Turku : University of Turku, 2012. 64 p.

Research output: ThesisDissertationCollection of Articles

TY - THES

T1 - Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting

T2 - Dissertation

AU - Pollari, Sirkku

N1 - TK401 SDA: BIC

PY - 2012

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N2 - Breast cancer that has metastasized to bone is currently an incurable disease, causing significant morbidity and mortality. The aim of this thesis work was to elucidate molecular mechanisms of bone metastasis and thereby gain insights into novel therapeutic approaches. First, we found that L-serine biosynthesis genes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) and phosphoserine phosphatase (PSPH), were up-regulated in highly bone metastatic MDA-MB-231(SA) cells as compared with the parental breast cancer cell line. Knockdown of serine biosynthesis inhibited proliferation of MDA-MB-231(SA) cells, and L-serine was essential for the formation of bone resorbing osteoclasts. Clinical data demonstrated that high expression of PHGDH and PSAT1 was associated with decreased relapse-free and overall survival and with features typical of poor outcome in breast cancer. Second, RNA interference screening pointed out heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for transforming growth factor ß (TGF-ß)-induced interleukin 11 (IL-11) production in MDA-MB-231(SA) cells. Exogenous heparan sulfate glycosaminoglycans heparin and K5-NSOS also inhibited TGF-ß-induced IL-11 production in MDA-MB-231(SA) cells. Furthermore, K5-NSOS decreased osteolytic lesion area and tumor burden in bone in mice. Third, we discovered that the microRNAs miR-204, -211 and -379 inhibited IL-11 expression in MDA-MB-231(SA) cells through direct targeting of the IL-11 mRNA. MiR-379 also inhibited Smad-mediated signaling. Gene expression profiling of miR-204 and -379 transfected cells indicated that these microRNAs down-regulate several bone metastasis-relevant genes, including prostaglandin-endoperoxide synthase 2 (PTGS2). Taken together, this study identified three potential treatment strategies for bone metastatic breast cancer: inhibition of serine biosynthesis, heparan sulfate glycosaminoglycans and restoration of miR-204/-211/-379.

AB - Breast cancer that has metastasized to bone is currently an incurable disease, causing significant morbidity and mortality. The aim of this thesis work was to elucidate molecular mechanisms of bone metastasis and thereby gain insights into novel therapeutic approaches. First, we found that L-serine biosynthesis genes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1) and phosphoserine phosphatase (PSPH), were up-regulated in highly bone metastatic MDA-MB-231(SA) cells as compared with the parental breast cancer cell line. Knockdown of serine biosynthesis inhibited proliferation of MDA-MB-231(SA) cells, and L-serine was essential for the formation of bone resorbing osteoclasts. Clinical data demonstrated that high expression of PHGDH and PSAT1 was associated with decreased relapse-free and overall survival and with features typical of poor outcome in breast cancer. Second, RNA interference screening pointed out heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for transforming growth factor ß (TGF-ß)-induced interleukin 11 (IL-11) production in MDA-MB-231(SA) cells. Exogenous heparan sulfate glycosaminoglycans heparin and K5-NSOS also inhibited TGF-ß-induced IL-11 production in MDA-MB-231(SA) cells. Furthermore, K5-NSOS decreased osteolytic lesion area and tumor burden in bone in mice. Third, we discovered that the microRNAs miR-204, -211 and -379 inhibited IL-11 expression in MDA-MB-231(SA) cells through direct targeting of the IL-11 mRNA. MiR-379 also inhibited Smad-mediated signaling. Gene expression profiling of miR-204 and -379 transfected cells indicated that these microRNAs down-regulate several bone metastasis-relevant genes, including prostaglandin-endoperoxide synthase 2 (PTGS2). Taken together, this study identified three potential treatment strategies for bone metastatic breast cancer: inhibition of serine biosynthesis, heparan sulfate glycosaminoglycans and restoration of miR-204/-211/-379.

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KW - bone metastasis

KW - L-serine

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KW - heparan sulfate glycosaminoglycan

KW - microRNA

KW - rintasyöpä

KW - luustoetäpesäke

KW - L-seriini

KW - hepariinisulfaatti

M3 - Dissertation

SN - 978-951-29-4961-8

T3 - Annales Universitatis Turkuensis: D Medica - Odontologica

PB - University of Turku

CY - Turku

ER -