Rescue of Cyclin D1 Deficiency by Knockin Cyclin E

Geng, Yan; Whoriskey, Wendy; Park, Mary Y; Bronson, Roderick T.; Medema, René H.; Li, Tiansen; Weinberg, Robert A.; Siciński, Piotr

doi:10.1016/s0092-8674(00)80788-6

Cited by 327 publications

(236 citation statements)

References 23 publications

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“…Interestingly, this altered response was not due to the massive deregulation of RB/E2F-target gene expression, but rather to perturbations that are known to directly influence CDK2 function. These findings are consistent with studies from genetic models, wherein the utilization of a particular CDK can be substituted by another (Geng et al, 1999). Seemingly, these controls are already somewhat compromised in MCF-10A cells, and this finding may in fact contribute to the pivotal requirement for Rb in eliciting acute cell-cycle inhibition in this model.…”

Section: Discussionsupporting

confidence: 88%

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

et al. 2010

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A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

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Section: Discussionsupporting

confidence: 88%

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

et al. 2010

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“…Future study is needed to explore whether the other major downstream property of cyclin D1/CDK4, e.g. sequestering the CDK inhibitor p27 Kip1 to trigger cyclin E-initiated Rb-independent S phase entry (Geng et al, 1999;Perez-Roger et al, 1999;Donnellan and Chetty, 1999), is associated with novel tumorigenic mechanisms caused by ampli®ed PIK3CA in cervical cancer development. Not mutually exclusive are the possibilities that, in cervical tumorigenesis, increased PIK3CA and elevated PI 3-kinase activity contribute to other AKT-involved growth-promoting pathways or antiapoptotic signal.…”

Section: Resultsmentioning

confidence: 99%

PIK3CA as an oncogene in cervical cancer

et al. 2000

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“…In our studies, we were unable to detect any difference in cyclin D2 and D3 expression between CERM and CERM D1À/À mammary glands. It has been shown that the genetic replacement of cyclin D1 with human cyclin E in transgenic mice rescues the cyclin D1-deficient phenotype (Geng et al, 1999). It is important to note that in these knock-in mice, the expression of human cyclin E is driven by the cyclin D1 promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin D1 and E are considered weak oncogenes since their overexpression results in the formation of long-latency mammary adenocarcinomas (Sutherland and Musgrove, 2004). In addition, these proteins seem to have redundant functions in mammary gland development since the cyclin D1 knockout phenotype can be rescued by genetic replacement with cyclin E (Geng et al, 1999). Previous studies showed that cyclin E overexpression causes DNA damage and checkpoint activation (Spruck et al, 1999;Ekholm-Reed et al, 2004;Bartkova et al, 2005;Minella et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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We have previously shown that increased and deregulated estrogen receptor a expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERa-mediated mammary tumorigenesis, we crossed ERa-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERa-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERa in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERa-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ERa-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ERa-overexpressing breast cancers.

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Rescue of Cyclin D1 Deficiency by Knockin Cyclin E

Cited by 327 publications

References 23 publications

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

PIK3CA as an oncogene in cervical cancer

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

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