Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting
Pollari, Sirkku (2012-04-14)
Dissecting the molecular mechanisms of breast cancer bone metastasis for therapeutic targeting
Pollari, Sirkku
(14.04.2012)
Annales Universitatis Turkuensis D 1008 Turun yliopisto
Julkaisun pysyvä osoite on:
https://urn.fi/URN:ISBN:978‐951‐29‐4962‐5
https://urn.fi/URN:ISBN:978‐951‐29‐4962‐5
Kuvaus
Siirretty Doriasta
Tiivistelmä
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 β (TGF‐β)‐induced interleukin 11 (IL‐11) production in MDA‐MB‐231(SA) cells.
Exogenous heparan sulfate glycosaminoglycans heparin and K5‐NSOS also inhibited
TGF‐β‐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.
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 β (TGF‐β)‐induced interleukin 11 (IL‐11) production in MDA‐MB‐231(SA) cells.
Exogenous heparan sulfate glycosaminoglycans heparin and K5‐NSOS also inhibited
TGF‐β‐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.
Kokoelmat
- Väitöskirjat [2771]