Prolactin as a Growth Factor in Breast Cancer

催乳素作为乳腺癌的生长因子

• 批准号: 8515942
• 负责人: Nira Ben-Jonathan
• 金额: $ 22.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515942
• 关键词: Abbreviations; Adipocytes; Adrenergic Receptor; Adverse effects; Agonist; Antineoplastic Agents; Apoptosis; Apoptotic; Arylsulfatases; Attention; BCL2 gene; Breast; Breast Cancer Cell; Bromocriptine; Cancer Patient; Cell Line; Cells; Cessation of life; Charcoal; Cisplatin; Clinical; Coupled; DNA Damage; DNA Repair; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Doxorubicin; Doxycycline; Drug Efflux; Drug Metabolic Detoxication; Drug resistance; Drug toxicity; Enzymes; Epithelial Cells; FDA approved; Fluorouracil; Glutathione S-Transferase; Goals; Growth Factor; Health; Hormones; Human; In Vitro; Inorganic Sulfates; Iodides; Isoproterenol; Ligands; MAP Kinase Gene; Mammary Gland Parenchyma; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Messenger RNA; Methotrexate; Microtubules; Necrosis; Nude Mice; Oral; Paclitaxel; Pathway interactions; Pharmaceutical Preparations; Pituitary Gland; Plasma; Production; Prolactin; Prolactin Receptor; Proteins; Resistance; Role; Safety; Serum; Source; T47D; TNF-related apoptosis-inducing ligand; Time; Treatment Failure; Tumor Suppressor Genes; Unspecified or Sulfate Ion Sulfates; Vinblastine; Visceral; autocrine; chemotherapeutic agent; chemotherapy; cytotoxicity; drug efficacy; improved; in vivo; malignant breast neoplasm; overexpression; paracrine; pituitary circulation; subcutaneous; success; tumor

DESCRIPTION (provided by applicant): Chemotherapy is the mainstay treatment for advanced breast cancer, but tumor resistance is a major obstacle that results in treatment failure. Resistance results from many causes, including drug efflux, inactivation, altered expression of pro/anti-apoptotic proteins or tumor suppressor genes, and increased DNA repair mechanisms. We present evidence that prolactin (PRL) serves as a survival factor which antagonizes the cytotoxicity of the DNA-damaging agents cisplatin and doxorubicin, and the microtubule disrupting agent taxol. PRL protects breast cancer cells (BCC) against drugs by activating the detoxification enzyme glutathione-S-transferase (GST) as well as by increasing the expression of the anti- apoptotic protein Bcl-2. The human breast receives PRL input from two sources: the pituitary and local. Within the breast, stromal adipocytes produce significantly more PRL than epithelial cells, and both are under tonic inhibition. We discovered expression of dopamine receptors (DAR) in breast tissue, adipocytes and BCC. Similar to their action on pituitary PRL, dopamine and bromocriptine (Br) suppress breast PRL production. Locally- produced PRL likely confers chemoresistance, since BCC with high endogenous PRL are more resistant to drugs than those with low PRL. Our newly developed LS14 human adipocyte cell line, which produces PRL and expresses the PRL receptor (PRL-R), is also resistant to many anticancer drugs. Hypothesis: PRL confers chemoresistance against different classes of anti-cancer drugs by activating detoxification enzymes, anti-apoptotic proteins or both. Input of PRL to breast tumors comes from the circulation (pituitary), paracrine (stromal adipocytes) and autocrine (BCC). Similar to its action on the pituitary, dopamine suppresses breast PRL and thus sensitizes breast cancer to anticancer drugs. Aim 1: To compare expression of PRL and PRL-R in BCC at both the mRNA and proteins levels, and use knockdown and overexpression to determine the role of local PRL in chemoresistance, Aim 2: To examine whether GST and/or Bcl-2 mediate chemoresistance by PRL against four classes of drugs: DNA-damaging, microtubule altering, anti-metabolites, and the death ligand TRAIL (tumor necrotic factor (TNF)-related apoptosis-inducing ligand). Aim 3: To characterize DAR in adipocytes, BCC and LS14 cells, and determine whether dopamine and its agonists suppress PRL production and increase cell sensitivity to anticancer drugs. Aim 4: To establish mixed-cultures of fully differentiated LS14 adipocytes and BCC and examine whether dopamine agonists sensitize LS14/BCC tumors in athymic mice to anticancer drugs. Clinical Impact: Oral dopamine agonists with an excellent record of safety and efficacy for suppressing PRL are FDA-approved. Their use in breast cancer patients undergoing chemotherapy should improve dru efficacy, lower the doses, reduce side effects and expand the choice of effective drugs. PUBLIC HEALTH RELEVANCE: This continuation study examines the mechanism by which prolactin, a hormone which is produced by both the pituitary gland and breast tissue, confers chemoresistance on breast cancer cells under in vitro and in vivo conditions. The long term goal is to establish FDA-approved, long acting dopamine agonists as suppressor or PRL secretion, resulting in increased efficacy of chemotherapeutic agents in breast cancer patients.

描述（申请人提供）：化疗是晚期乳腺癌的主要治疗方法，但肿瘤耐药性是导致治疗失败的主要障碍。耐药性由多种原因引起，包括药物外流、失活、促/抗凋亡蛋白或肿瘤抑制基因的表达改变以及 DNA 修复机制增强。我们提供的证据表明，催乳素 (PRL) 作为一种生存因子，可以拮抗 DNA 损伤剂顺铂和阿霉素以及微管破坏剂紫杉醇的细胞毒性。 PRL 通过激活解毒酶谷胱甘肽-S-转移酶 (GST) 以及增加抗凋亡蛋白 Bcl-2 的表达来保护乳腺癌细胞 (BCC) 免受药物侵害。人类乳房从两个来源接收 PRL 输入：垂体和局部。在乳房内，基质脂肪细胞比上皮细胞产生明显更多的 PRL，并且两者都受到强直抑制。我们发现乳腺组织、脂肪细胞和基底细胞癌中存在多巴胺受体 (DAR) 表达。与它们对垂体 PRL 的作用类似，多巴胺和溴隐亭 (Br) 抑制乳房 PRL 的产生。本地产生的 PRL 可能会产生化疗耐药性，因为具有高内源性 PRL 的 BCC 比具有低 PRL 的 BCC 更能耐受药物。我们新开发的LS14人类脂肪细胞系可产生PRL并表达PRL受体（PRL-R），也对许多抗癌药物具有耐药性。假设：PRL 通过激活解毒酶、抗凋亡蛋白或两者来赋予针对不同类别抗癌药物的化学耐药性。 PRL 向乳腺肿瘤的输入来自循环（垂体）、旁分泌（基质脂肪细胞）和自分泌（BCC）。与其对垂体的作用类似，多巴胺会抑制乳房 PRL，从而使乳腺癌对抗癌药物敏感。目标 1：比较 BCC 中 PRL 和 PRL-R 在 mRNA 和蛋白质水平上的表达，并使用敲低和过表达来确定局部 PRL 在化疗耐药中的作用，目标 2：检查 GST 和/或 Bcl-2 是否通过 PRL 介导针对四类药物的化疗耐药：DNA 损伤、微管改变、抗代谢物和死亡配体 TRAIL（肿瘤坏死因子） （TNF）相关的凋亡诱导配体）。目标 3：表征脂肪细胞、BCC 和 LS14 细胞中的 DAR，并确定多巴胺及其激动剂是否抑制 PRL 产生并增加细胞对抗癌药物的敏感性。目标 4：建立完全分化的 LS14 脂肪细胞和 BCC 的混合培养物，并检查多巴胺激动剂是否使无胸腺小鼠的 LS14/BCC 肿瘤对抗癌药物敏感。临床影响：口服多巴胺激动剂在抑制 PRL 方面具有良好的安全性和有效性，已获得 FDA 批准。它们在接受化疗的乳腺癌患者中的使用应该可以提高药物疗效、降低剂量、减少副作用并扩大有效药物的选择。公共健康相关性：这项持续研究探讨了催乳素（一种由垂体和乳腺组织产生的激素）在体外和体内条件下赋予乳腺癌细胞化疗耐药性的机制。长期目标是建立 FDA 批准的长效多巴胺激动剂作为 PRL 分泌抑制剂，从而提高乳腺癌患者化疗药物的疗效。

项目成果

The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma.

• DOI: 10.1016/j.canlet.2015.10.024
• 发表时间: 2016-01-28
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Tuttle TR;Mierzwa ML;Wells SI;Fox SR;Ben-Jonathan N
• 通讯作者: Ben-Jonathan N

Calcium sensing receptor activation elevates proinflammatory factor expression in human adipose cells and adipose tissue.

• DOI: 10.1016/j.mce.2012.03.006
• 发表时间: 2012-09-25
• 期刊: MOLECULAR AND CELLULAR ENDOCRINOLOGY
• 影响因子: 4.1
• 作者: Cifuentes, Mariana;Fuentes, Cecilia;Tobar, Nicolas;Acevedo, Ingrid;Villalobos, Elisa;Hugo, Eric;Ben-Jonathan, Nira;Reyes, Marcela
• 通讯作者: Reyes, Marcela