؊/؊ mouse embryonic fibroblasts, elevated CDK2 activity increased wild-type (wt) but not S400A PR transcriptional activity in the absence of progestin. CDK2 induced nuclear localization of unliganded wt but not S400A PR; liganded S400A PR exhibited delayed nuclear accumulation. These studies demonstrate that CDK2 regulates PR in the absence of progestins via phosphorylation of Ser400, thus revealing a novel mechanism for upregulated PR transcriptional activity in human breast cancer cells expressing altered cell cycle regulatory molecules.The steroid hormones estrogen and progesterone regulate breast development (29, 89) and contribute to breast cancer progression (29,54). Breast cancer cell lines are used to model the effects of steroid hormones on cell proliferation and survival. Steroidal control of cell cycle progression takes place at defined points in the G 1 phase of the cell cycle (52). Progesterone has either stimulatory (25, 47) or biphasic (11,23,53) effects on human T47D breast cancer cell growth, dependent in part upon cell culture conditions and the presence of estrogenic stimuli. Cell cycle analyses of biphasic cell growth patterns indicate that following a single dose of progesterone, cyclin D1 and cyclin E levels initially increase as cells undergo S-phase entry. Cyclin-dependent protein kinase 2 (CDK2) activity peaks at approximately 16 h. Coincident with increased CDK2 activity, progesterone receptor (PR) protein levels begin to decline. The CDK inhibitors p21 and p27 are then induced after this early proliferative phase, leading to G 1 arrest, and PR levels slowly recover as cells exit the mitotic cell cycle. Cells are further growth inhibited in the presence of additional progesterone treatments (23, 53), but progestinprimed cells can be induced to grow by administration of growth factors (23). These studies demonstrate a complex interplay between PR and cell cycle regulators.Several studies have demonstrated that cyclin D1 and p27 play important roles in normal mammary gland development (14,49,81,82). Cyclin D1 Ϫ/Ϫ mice have a deficiency in pregnancy-associated mammary gland development (16, 80). In addition, overexpression of cyclins D1 and E and decreased expression of the CDK inhibitor p27 are associated with the high growth rates seen in human breast cancers. For example, approximately 45 to 50% of breast cancers overexpress cyclin D1 (5, 21). Furthermore, progression from normal breast tissue through invasive ductal carcinoma (77), high-grade ductal carcinoma relative to low grade (77), and late-stage lesions (34) are all associated with increased expression of cyclin E. In addition, decreased expression of p27 occurs in 30% of breast cancers and is correlated with poor prognosis in primary breast cancers (7,63,87). Mouse models of breast cancer support a role for alterations in cell cycle molecules in progression of mammary epithelial cells to preneoplastic stages (69). Deregulated cell cycle molecules are predicted to augment breast cancer progression in part as a result of increased...

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The product of antibody affinity and concentration, which we define as antibody capacity (CAP = K(A) x IgE), is more informative with regard to describing allergen sensitivity than antibody concentration alone. Antibody binding capacity provides physiological evidence of atopy in some subjects who do not test positively by common methods and suggests an affinity threshold to produce a positive SPT reaction.

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