piperidines and Carcinoma--Ductal--Breast

The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N=5,252) or low bone mass (N=4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95% CI 0.25-0.68, P<0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95% CI 0.14-0.63, P=0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95% CI 0.13-0.71, P=0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction=0.31) and between low bone mass and osteoporosis groups (P interaction=0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Ductal, Breast; Double-Blind Method; Female; Fractures, Bone; Humans; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Risk Factors; Thiophenes

It has been demonstrated that certain NK-1 antagonists could reduce proliferation of several cancer cell lines, however, it is unknown whether SR140333 exerts proliferation inhibition in breast cancer cell line.. Immunohistochemical staining was carried out to investigate the immunolocation of NK-1 in breast cancer tissues and T47D cell line, thereafter, various concentrations of [Sar9, Met(O2)11]substance P and SR140333 were applied alone or combined. MTT assay was applied to detect cytoactivation and coulter counter was to detect growth curve. The Hoechst33258 staining was performed to detect apoptosis.. We found that breast cancer and T47D cells bear positive expression of NK-1. SR140333 inhibited cell growth in a dose dependent manner. Furthermore, SR140333 could counteract [Sar9, Met(O2)11]substance P induced proliferation. Hoechst33258 staining revealed the presence of apoptosis after SR140333 treatment.. Our study demonstrated SR140333 exert proliferation inhibition in breast cancer cell line T47D and indicates NK-1 play a central role in the substance P related cell proliferation in breast cancer.

Topics: Antigens, Ly; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Proliferation; Female; Humans; Immunoenzyme Techniques; NK Cell Lectin-Like Receptor Subfamily B; Piperidines; Quinuclidines; Tumor Cells, Cultured

Endothelins (ET-1, ET-2 and ET-3) are 21-amino acid vasoactive peptides that bind to G-protein-linked transmembrane receptors, ET-RA and ET-RB. As well as modulating vasoconstriction, endothelins regulate growth in several cell types and may also affect differentiation, inflammation and angiogenesis. Both macrophages and endothelins are found in areas of hypoxia in solid tumors and ET-2 expression may be modulated by hypoxia in some tumors. As the peptide structure of mature endothelins is similar to that of CXC chemokines, we asked if endothelins contribute to control of macrophage distribution in tumors. We found that ET-2 is a chemoattractant for macrophages and THP-1 monocytic cells, but not for freshly isolated monocytes. The chemotactic response to ET-2 shows a typical bell-shaped response curve. Experiments with endothelin receptor antagonists showed that migration to ET-2 is mediated via the ET-RB receptor. Moreover, monocytes do not express ET-RB. Chemotaxis towards ET-2 is via the MAPK pathway: p44 and p42 are phosphorylated when THP-1 cells are stimulated with ET-2, and the MAPKK inhibitor PD98059 stops chemotaxis. As with 'classical' chemokines, migration toET-2 is also inhibited by hypoxia and by pertussis toxin. As well as its chemotactic properties, ET-2 leads to activation of macrophages. In human breast tumors that express ET-2, endothelins and ET-RB expressing macrophages often co-localized. While shorter than 'classical' chemokines, ET-2 shares a similar peptide sequence with chemokines and may signal via a similar receptor and MAPK-mediated pathway. Furthermore, ET-2 expression by tumors may modulate the behavior of macrophages such that activated cells accumulate in areas of hypoxia.

Topics: Bacterial Proteins; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Hypoxia; Cell Line; Chemokines, CXC; Chemotactic Factors; Chemotaxis; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Enzyme Inhibitors; Female; Flavonoids; Humans; Macrophage Activation; Macrophages; MAP Kinase Signaling System; Membrane Proteins; Monocytes; Neoplasm Proteins; Oligopeptides; Peptides, Cyclic; Phosphorylation; Piperidines; Protein Processing, Post-Translational; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Structure-Activity Relationship

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Estrogen Antagonists; Female; Humans; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Tamoxifen