piperidines and Carcinoma-in-Situ

Although tamoxifen appears to markedly reduce breast cancer risk in women with a prior diagnosis of atypical hyperplasia or in situ carcinoma, it is not clear what other groups of women receive substantial benefit. Major breast chemoprevention priorities are to (1) develop new agents that (a) have fewer side effects, (b) are effective in ER--as well as tamoxifen-resistant precancerous tissue, and (c) are compatible with hormone therapy; and (2) develop efficient clinical strategies including prognostic and predictive morphologic and molecular biomarkers. Breast tissue may be repeatedly sampled for evidence of intraepithelial neoplasia by fine needle aspiration, ductal lavage, or needle biopsy to select candidates at highest short-term risk as well as to monitor response in small proof of principle studies prior to a large cancer incidence trial. Molecular marker expression may also be used to select a cohort most likely to respond to a particular agent. A large number of new agents are attractive as potential prevention agents and some are already in clinical prevention testing. Compounds which should be effective in ER + precancerous tissue but may have a better side-effect profile include new selective estrogen receptor modulators which lack uterine estrogen agonist activity, isoflavones, aromatase inactivators/inhibitors for postmenopausal women, and gonadotropin-releasing hormone regimens for premenopausal women. Retinoids, rexinoids, and deltanoids may be efficacious in ER+ tissue resistant to tamoxifen. Agents which should theoretically have activity in ER- or ER+ precancerous tissue include polyamine synthesis inhibitors, tyrosine kinase inhibitors, combined demethylating agents and histone deacetylase inhibitors, as well as metalloprotease and angiogenesis inhibitors. Sample Phase I and Phase II clinical trial designs are reviewed using modulation of molecular markers and breast intraepithelial neoplasia as the major endpoints.

Topics: Aneuploidy; Angiogenesis Inhibitors; Anticarcinogenic Agents; Apoptosis; Aromatase Inhibitors; Breast Neoplasms; Carcinoma in Situ; Clinical Trials, Phase II as Topic; Cyclooxygenase Inhibitors; Disease Progression; Eflornithine; Endpoint Determination; Enzyme Inhibitors; Estrogens; Female; Fenretinide; Gonadotropin-Releasing Hormone; Humans; Hyperplasia; Isoflavones; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Phenotype; Piperidines; Polyamines; Precancerous Conditions; Protein-Tyrosine Kinases; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Thiophenes; Uterine Neoplasms

The fallopian tube epithelium is one of the potential sources of high-grade serous ovarian cancer (HGSC). The use of estrogen only hormone replacement therapy increases ovarian cancer (OVCA) risk. Despite estrogen's influence in OVCA, selective estrogen receptor modulators (SERMs) typically demonstrate only a 20 % response rate. This low response could be due to a variety of factors including the loss of estrogen receptor signaling or the role of estrogen in different potential cell types of origin. The response of fallopian tube epithelium to SERMs is not known, and would be useful when determining therapeutic options for tumors arising from this cell type, such as HGSC.. Using normal murine derived oviductal epithelial cells (mouse equivalent to the fallopian tube) estrogen receptor expression was confirmed and interaction with its ligand, estradiol, triggered mRNA and protein induction of progesterone receptor (PR). The SERMs 4-hydroxytamoxifen, raloxifene and desmethylarzoxifene, functioned as estrogen receptor antagonists in oviductal cells. Cellular proliferation and migration assays suggested that estradiol does not significantly impact cellular migration and increased proliferation. Further, using RNAseq, the oviduct specific transcriptional genes targets of ER when stimulated by estradiol and 4-hydroxytamoxifen signaling were determined and validated. The RNA-seq revealed enrichment in proliferation, anti-apoptosis, calcium signaling and steroid signaling processes. Finally, the ER and PR receptor status of a panel of HGSC cell lines was investigated including Kuramochi, OVSAHO, OVKATE, OVCAR3, and OVCAR4. OVSAHO demonstrated receptor expression and response, which highlights the need for additional models of ovarian cancer that are estrogen responsive.. Overall, the fallopian tube has specific gene targets of estrogen receptor and demonstrates a tissue specific response to SERMs consistent with antagonistic action.

Topics: Animals; Antineoplastic Agents, Hormonal; Carcinoma in Situ; Cell Line, Tumor; Drug Resistance, Neoplasm; Estradiol; Estrogen Antagonists; Estrogens; Fallopian Tubes; Female; Gene Expression Regulation, Neoplastic; Genome; Humans; Mice; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Piperidines; Raloxifene Hydrochloride; Receptors, Estrogen; Tamoxifen; Thiophenes; Transcriptome

Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue. This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis. Vascular endothelial cell growth factor (VEGF) is a potent angiogenic growth factor, commonly involved in tumor-induced angiogenesis. Here, we show that both VEGF and VEGFR2 expression increase with histological progression to invasive disease in the rat 7,12-dimethylbenz[a]anthracene (DMBA) model. Other VEGF receptors, VEGFR1, neuropilin 1 and neuropilin 2, are constitutively expressed throughout progression. To examine whether VEGF signaling is functionally relevant to tumor-induced endothelial tubule formation in vitro and for tumor formation in vivo, we utilized the VEGFR2 inhibitor, ZD6474. In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA-treated rats is inhibited by ZD6474, in a dose-dependent fashion. The administration of ZD6474 to DMBA-treated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95% (P < 0.05), when administered 1 week or 6 weeks post-DMBA initiation. Invasive disease was absent in all ZD6474 cohorts. These data support the hypothesis that progression of DMBA-induced preinvasive mammary pathologies to palpable disease requires angiogenesis via a VEGF-dependent mechanism.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Base Sequence; Carcinoma in Situ; DNA Primers; Female; Humans; Hyperplasia; Mammary Neoplasms, Experimental; Neovascularization, Pathologic; Piperidines; Quinazolines; Rats; Rats, Sprague-Dawley; Vascular Endothelial Growth Factor Receptor-2

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