Endocrine dysfunction in p27Kip1 deficient mice and susceptibility to Wnt-1 driven breast cancer.
The cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) (p27) is a marker of prognosis in many cancers, including breast cancer. Low p27 expression correlates with poor prognosis, especially in hormone receptor positive breast tumors. This association suggests a role for p27 in hormone-dependent cancer. We used the Wnt-1 transgenic mouse model to further explore the role of p27 in hormone-driven breast cancer. We found that p27 deficiency did not alter breast cancer rate in either male or female Wnt-1 mice. However, we did find p27-/- females had reduced levels of serum progesterone (P) and increased variability in estradiol (E), which could have affected their cancer susceptibility. To equalize hormone levels, an additional cohort of Wnt-1 female mice was ovariectomized and implanted with slow release pellets of E and P. Although this treatment did not alter the breast cancer rate, it did accelerate the development of pituitary and gastric tumors in p27-/- mice. This study shows that while not a significant inhibitor of Wnt-1-driven breast cancer, p27 inhibits gastric tumors, whose latency is modulated by sex steroids.
Glover
Cynthia E
CE
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Gurley
Kay E
KE
Kim
Kyung-Hoon
KH
Storer
Barry
B
Fero
Mathew L
ML
Kemp
Christopher J
CJ
D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000097:blood* / Q000494:pharmacology; D005260:Female; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000097:blood* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009376:Neoplasms, Hormone-Dependent / Q000097:blood* / Q000473:pathology; D010052:Ovariectomy; D010911:Pituitary Neoplasms / Q000378:metabolism / Q000473:pathology; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011374:Progesterone; D004958:Estradiol