Prolactin: mammary progenitors and tumor initiating cells in luminal carcinomas

催乳素：乳腺祖细胞和管腔癌中的肿瘤起始细胞

• 批准号: 8469745
• 负责人: LINDA A. SCHULER
• 金额: $ 28.97万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469745
• 关键词: Address; Adjuvant; Basal Cell; Behavior; Biological Assay; Cancerous; Carcinoma; Cells; Characteristics; Common Neoplasm; Dependence; Dependency; Development; Diagnostic; Dissection; Epithelial; Estrogen Antagonists; Estrogen Receptor alpha; Female; Goals; Hormonal; Hormones; Immunocompetent; Lead; Lesion; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediator of activation protein; Modeling; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Ovarian; Pathogenesis; Patients; Pre-Clinical Model; Predisposition; Process; Prolactin; Recurrence; Regulation; Resistance; Role; Sampling; Signal Transduction; Stem cells; Steroids; Surface; Testing; Therapeutic; Transcript; Transgenic Mice; Transplantation; Tumor Subtype; Woman; cancer stem cell; conventional therapy; design; improved; in vivo Model; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel therapeutic intervention; progenitor; therapy development; tumor; tumor initiation

DESCRIPTION (provided by applicant): 75% of all breast tumors in women express estrogen receptor alpha (ER?+). Although anti-estrogens have markedly reduced mortality for many women with this "luminal" tumor subtype, one quarter of these patients eventually succumb to anti-estrogen-resistant cancer. Tumor initiating cells, or "cancer stem cells" have been implicated in resistance to conventional therapies, recurrence and metastasis. However, the origin of luminal tumors and the characteristics of the cells that defy treatment remain unknown. Mouse models of ER?+ breast cancer that would facilitate these studies are very rare. Multiple studies point to a close link between prolactin (PRL), aand the pathogenesis and therapeutic responsiveness of ER?+ breast cancer. Our in vivo model, the NRL-PRL transgenic mouse, permits dissection of the dynamic processes that lead to diverse carcinomas with transcript profiles that resemble the luminal tumor subtype in women, including ER? expression. In this new application, we will employ this model to investigate the hypothesis that PRL cooperates with ovarian steroids to modulate mammary epithelial progenitor and tumor cell subpopulations, promoting the development of luminal carcinomas. Further, these tumors contain tumor initiating cells, which display hormonal dependencies and therapeutic susceptibilities distinct from the bulk of tumor cells. In Aim 1, we will establish the effect of PRL and crosstalk with ovarian steroids on mammary epithelial subpopulations in nonparous females prior to lesions, as defined by surface markers and functional progenitor assays, and identifies key mediators of these processes. In Aim 2, we will determine characteristics of tumor initiating cells in PRL-induced ER?+ carcinomas, and ascertain their dependence on PRL and ovarian steroids and susceptibility to adjuvant treatment. In Aim 3, we will elucidate interplay between PRL and a well-characterized oncogenic signal, ?-catenin, in regulation of normal mammary subpopulations and tumor subtype by examining the net effect of crosstalk on epithelial subpopulations prior to lesions, in early lesions, and carcinomas. These studies will illuminate the mechanism(s) whereby PRL interacts with endogenous steroids and oncogenes to promote the luminal breast cancer subtype, and its role in treatment sensitivity. They will test the cancer stem cell hypothesis in PRL-induced ER?+ carcinomas, generating a new and biologically relevant paradigm for understanding this prevalent tumor subtype, enabling the design of novel therapeutic approaches.

描述（由申请人提供）：75%的女性乳腺肿瘤表达雌激素受体α（ER？+）。尽管抗雌激素药物显着降低了许多患有这种“腔内”肿瘤亚型的女性的死亡率，但这些患者中有四分之一最终死于抗雌激素药物耐药性癌症。肿瘤起始细胞或“癌症干细胞”与传统疗法的抵抗、复发和转移有关。然而，管腔肿瘤的起源和无法治疗的细胞的特征仍然未知。有助于这些研究的 ER+ 乳腺癌小鼠模型非常罕见。多项研究指出催乳素 (PRL)、a 与 ER?+ 乳腺癌的发病机制和治疗反应之间存在密切联系。我们的体内模型 NRL-PRL 转基因小鼠可以剖析导致多种癌症的动态过程，其转录谱类似于女性的管腔肿瘤亚型，包括 ER？表达。 在这个新的应用中，我们将利用这个模型来研究以下假设：PRL 与卵巢类固醇协同调节乳腺上皮祖细胞和肿瘤细胞亚群，促进管腔癌的发展。此外，这些肿瘤含有肿瘤起始细胞，其表现出与大部分肿瘤细胞不同的激素依赖性和治疗敏感性。在目标 1 中，我们将根据表面标记物和功能祖细胞测定确定 PRL 以及与卵巢类固醇的串扰对未产雌性病变前乳腺上皮亚群的影响，并确定这些过程的关键介质。在目标 2 中，我们将确定 PRL 诱导的 ER?+ 癌中肿瘤起始细胞的特征，并确定它们对 PRL 和卵巢类固醇的依赖性以及对辅助治疗的敏感性。在目标 3 中，我们将通过检查病变前、早期病变和癌症中上皮亚群串扰的净效应，阐明 PRL 和一种明确表征的致癌信号 β-连环蛋白在正常乳腺亚群和肿瘤亚型调节中的相互作用。 这些研究将阐明 PRL 与内源性类固醇和癌基因相互作用以促进管腔乳腺癌亚型的机制，及其在治疗敏感性中的作用。他们将在 PRL 诱导的 ER?+ 癌中测试癌症干细胞假说，产生一种新的生物学相关范例来了解这种普遍的肿瘤亚型，从而能够设计新的治疗方法。