Cyclin D1 provides a link between development and oncogenesis in the retina and breast

Abstract

Mice lacking cyclin D1 have been generated by gene targeting in embryonic stem cells. Cyclin D1-deficient animals develop to term but show reduced body size, reduced viability, and symptoms of neurological impairment. Their retinas display a striking reduction in cell number due to proliferative failure during embryonic development. In situ hybridization studies of normal mouse embryos revealed an extremely high level of cyclin D1 in the retina, suggesting a special dependence of this tissue on cyclin D1. In adult mutant females, the breast epithelial compartment fails to undergo the massive proliferative changes associated with pregnancy despite normal levels of ovarian steroid hormones. Thus, steroid-induced proliferation of mammary epithelium during pregnancy may be driven through cyclin D1.

Loss of cyclin D1 in concert with deregulated estrogen receptor α expression induces DNA damage response activation and interrupts mammary gland morphogenesis

“…Loss of cyclin D1 completely interrupted mammary gland development in CERM mice Cyclin D1 is not required for pubertal mammary gland development in mice that have normal ERa expression levels (Fantl et al, 1995;Sicinski et al, 1995). However, when loss of cyclin D1 was introduced in mice with deregulated ERa expression (CERM D1À/À mice), mammary gland development was interrupted.…”

“…A cohort of CERM D1À/À mice were maintained on doxycycline until 3 weeks of age when they were moved to regular diet until they were euthanized at 6 weeks of age. Mice were genotyped using PCR-based assays previously described (Sicinski et al, 1995;Frech et al, 2005). Mice were maintained under the guidelines approved by the Georgetown University Animal Care and Use Committee.…”

“…The cyclin E protein is overexpressed in approximately 40% of breast cancers while gene amplifications are rare (Sutherland and Musgrove, 2004). Cyclin D1 knockout mice undergo normal pubertal mammary gland development but they fail to develop lobuloalveolar structures during pregnancy (Fantl et al, 1995;Sicinski et al, 1995). Cyclin D1 appears to play a very specific role in mammary gland development since the lobuloalveolar defect in cyclin D1 knockout mice occurs even in the presence of cyclin D2 and D3 overexpression (Yu et al, 2001).…”

Developmental defects and tumor predisposition in Rb mutant mice

“…The importance of pocket proteins in controlling proliferation during retina development is further demonstrated by the analysis of cyclin D1-de®cient mice (Sicinski et al, 1995). Overall, cyclin D1 knockout mice are smaller which may be a consequence of reduced pRb phosphorylation.…”

Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

“…The weak expression of cyclins D1 and D2 is probably not the consequence of a di erence in staining e ciency with the three antibodies: (1) in other systems, these antibodies (DCS 6, DCS 3.1) reveal much higher levels of cyclin D1 and D2 (Lukas et al, 1994a(Lukas et al, , 1995a; (2) in vitro results with these but also other antibodies against D-type cyclins have also shown a higher level of cyclin D3 in dog thyroid cells (Depoortere et al, 1998); (3) analysis of D-type cyclin mRNA transcripts have shown a similar prevalence of cyclin D3 in control thyroids ( Figure 3); (4) blocking antibodies microinjection experiments demonstrated that cyclin D3 was the only D-type cyclin important for TSH-induced dog thyroid cell proliferation (Depoortere et al, 1998). A prominent role of cyclin D3 in thyroid, as compared to the other D-type cyclins, is also compatible with the fact that in mice lacking cyclins D1 or D2, the thyroid develops normally (Sicinski et al, 1995. It will be of interest to investigate whether cyclin D3 knock out mice will exhibit a thyroid phenotype consistent with a predominant role of this protein on thyroid cell proliferation and/or di erentiation.…”