Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cks1 plays an essential role in SCFSkp2-mediated ubiquitination, and consequently turnover, of the cdk2 inhibitor and tumor supressor p27Kip1. High Cks1 expression is associated with aggressive breast tumors and correlates with low p27Kip1 levels in some cases, although it is also an independent prognostic marker for survival, and provides predictive information in addition to that provided by p27Kip1 alone. In this report we demonstrate that Cks1 protein and mRNA are elevated to very high levels in mammary tumors initiated by erbB2, c-myc and polyoma middle-T (PyMT) in transgenic mice, whereas Cks1 protein is hardly detectable in the normal mammary epithelium. Cks1 is also highly upregulated in rat mammary tumors initiated by methylnitrosourea (MNU). Despite high levels of Cks1 expression, p27Kip1 levels were not reduced, and were in fact slightly higher in mammary tumors initiated by erbB2, PyMT and MNU. In contrast mammary tumors from MMTV-c-myc mice did exhibit low p27Kip1 and higher levels of Skp2. Together, these data suggest that deregulated Cks1 expression might play roles in oncogene and carcinogen-initiated mammary tumorigenesis independent of p27Kip1 turnover in certain tumors. Stable overexpression of Cks1 in human breast carcinoma MCF-7 cells did not significantly reduce p27Kip1 expression, although it conferred resistance to Faslodex (ICI 182780)-mediated inhibition of colony outgrowth in these cells. In contrast, Cks1-depleted MCF-7 cells formed fewer colonies in estrogen-containing medium. Therefore, our studies also suggest that Cks1 levels regulate the responsiveness of ER+ breast cancers to estrogens and anti-estrogens.
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PMID:High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1. 1936 Mar 56

Antiestrogen resistance often develops with prolonged exposure to hormone therapies, including tamoxifen, and is a major problem in the treatment of breast cancer. Understanding the mechanisms involved in the development of antiestrogen resistance is an important step in the development of new targeted therapies. Two forms of antiestrogen resistance exist: de novo resistance and acquired resistance. To mimic acquired resistance, we have established a tamoxifen-resistant breast cancer cell line (MCF-7TamR) by treating parental MCF-7 cells with tamoxifen over a period of 6 months to select for cells with the resistant phenotype. Characterization of the MCF-7TamR cells under normal, hormone-deprived, and tamoxifen-treated conditions suggests that these cells continue to grow in the presence of tamoxifen. Additionally, a greater percentage of resistant cells enter the S phase under tamoxifen conditions, compared with parental MCF-7 cells. Consistent with these growth results, molecular analysis indicates that tamoxifen-resistant cells express higher levels of cyclin E1, cdk2, ACTR, and E2F1. Faslodex or ICI 182, 780 (ICI)-mediated degradation of estrogen receptor (ER) reduced the proliferation of these cells, as well as the level of E2F1 expression in tamoxifen-resistant cells, suggesting that tamoxifen resistance and E2F1 expression are in part dependent on ER. We further showed that tamoxifen enhances the ERalpha/Sp-1 interaction and promotes the recruitment of ERalpha and Sp-1 to the proximal promoter of E2F1 in resistant cells. Collectively, our findings suggest that tamoxifen resistance is a result of increased ERalpha/Sp-1 interaction, which enhances the expression of E2F1 to promote tamoxifen resistance.
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PMID:Estrogen receptor regulates E2F1 expression to mediate tamoxifen resistance. 2021 21

Breast cancer is a classical hormone-dependent tumour; therefore, endocrine therapy is the mainstay of treatment for hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer. Until recently, classical endocrine agents such as tamoxifen, steroidal and nonsteroidal aromatase inhibitors and fulvestrant have been widely used in postmenopausal patients to treat locally advanced or metastatic disease. However, for patients with this subtype of breast cancer, the landscape of endocrine therapy is rapidly changing. Therapies targeting oestrogen modulation have evolved in recent years following the introduction of targeted agents, mTOR and CDK 4/6 inhibitors that are administered in combination with hormone therapy. As a result, options for endocrine therapy have expanded in recent years, and a variety of single-agent or combinations of targeted drugs and endocrine therapies are accepted. Fulvestrant is a selective oestrogen receptor downregulator (SERD) which was introduced to clinical practice in 2002, initially with the indication to treat postmenopausal women with hormone-receptor-positive advanced breast cancer as second-line therapy postdisease progression after aromatase inhibitors or tamoxifen. Additionally, fulvestrant has also been shown to be active in patients previously untreated with endocrine therapy, either both in the neoadjuvant and the metastatic setting, alone or in combination with other targeted therapies. Currently, the standard dose is 500 mg, which is administered with a loading dose. Fulvestrant received a new FDA indication in December 2016, in combination with palbociclib, both in pre/peri/postmenopausal women with breast cancer progressing after endocrine therapy. This manuscript aims to give an overview of new efficacy data and the current role of fulvestrant in the systemic therapy of hormone-receptor-positive advanced breast cancer, in the context of other available therapeutic modalities.
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PMID:Fulvestrant in advanced breast cancer: evidence to date and place in therapy. 2934 9

Male breast cancer occurs rarely, comprising <1% of breast cancers. Due to the low incidence of male breast cancer, clinical trials of this disease are lacking. Therefore, therapeutic strategies utilized in the management of female breast cancer are often applied to male patients with breast cancer. Specifically, clinical outcomes using CDK 4/6 inhibitors require further investigation in male patients. To the best of our knowledge, the present report presents the first known case of a male patient treated with second line Abemaciclib, Lupron and Fulvestrant, producing complete remission. To the best of our knowledge this is also the first report of complete remission in a male breast cancer patient with a regimen utilizing a CDK 4/6 inhibitor.
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PMID:Male patient with metastatic stage IV breast cancer achieves complete remission on second line Abemaciclib, Fulvestrant and Leuprolide: A case report. 3192 82