Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells.
Although mutations in the parkin gene are frequently associated with familial Parkinsonism, emerging evidence suggests that parkin also plays a role in cancers as a putative tumor suppressor. Supporting this, we show here that parkin expression is dramatically reduced in several breast cancer-derived cell lines as well as in primary breast cancer tissues. Importantly, we found that ectopic parkin expression in parkin-deficient breast cancer cells mitigates their proliferation rate both in vitro and in vivo, as well as reduces the capacity of these cells to migrate. Cell cycle analysis revealed the arrestment of a significant percentage of parkin-expressing breast cancer cells at the G1-phase. However, we did not observe significant changes in the levels of the G1-associated cyclin D1 and E. On the other hand, the level of cyclin-dependent kinase 6 (CDK6) is dramatically and selectively elevated in parkin-expressing breast cancer cells, the extent of which correlates well with the expression of parkin. Interestingly, a recent study demonstrated that CDK6 restrains the proliferation of breast cancer cells. Taken together, our results support a negative role for parkin in tumorigenesis and provide a potential mechanism by which parkin exerts its suppressing effects on breast cancer cell proliferation.
Tay
Shiam-Peng
SP
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore 308433, Singapore.
Yeo
Calvin W S
CW
Chai
Chou
C
Chua
Pei-Jou
PJ
Tan
Hui-Mei
HM
Ang
Alex X Y
AX
Yip
Daniel L H
DL
Sung
Jian-Xiong
JX
Tan
Puay Hoon
PH
Bay
Boon-Huat
BH
Wong
Siew-Heng
SH
Tang
Carol
C
Tan
Jeanne M M
JM
Lim
Kah-Leong
KL
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D051361:Cyclin-Dependent Kinase 6