Targeted disruption of the murine p27(Kip1) gene caused a gene dose-dependent increase in animal size without other gross morphologic abnormalities. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thymic hyperplasia was associated with increased T lymphocyte proliferation, and T cells showed enhanced IL-2 responsiveness in vitro. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. In the spleen, the absence of p27 selectively enhanced proliferation of hematopoietic progenitor cells. p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia, suggesting that p27 and Rb function in the same regulatory pathway. The absence of p27 also caused an ovulatory defect and female sterility. Maturation of secondary ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired.

Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.

Mutations in certain genes that regulate the cell cycle, such as p16 and p53, are frequently found in human cancers. However, tumor-specific mutations are uncommon in genes encoding cyclin E and the CDK inhibitor p27Kip1, two cell-cycle regulators that are also thought to contribute to tumor progression. It is now known that levels of both cyclin E and p27 can be controlled by posttranscriptional mechanisms, indicating that expression of these proteins can be altered by means other than simply mutation of their respective genes. Thus, changes in p27 and cyclin E protein levels in tumors might be more common than previously anticipated and may be indicators of tumor behavior.