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: 8298139
• 负责人: LINDA A. SCHULER
• 金额: $ 30.81万
• 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/8298139
• 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）：女性的所有乳腺肿瘤中有75％表达雌激素受体α（ER？+）。尽管抗雌激素的死亡率显着降低了许多具有这种“腔”肿瘤亚型的女性，但这些患者中有四分之一最终屈服于抗雌激素的癌症。引发细胞或“癌症干细胞”的肿瘤已与对常规疗法，复发和转移的抗性有关。但是，腔肿瘤的起源和反对治疗的细胞的特征仍然未知。 ER？+乳腺癌的小鼠模型会促进这些研究非常罕见。多项研究指出，催乳素（PRL）之间存在密切的联系，以及ER？+乳腺癌的发病机理和治疗反应性。我们的体内模型NRL-PRL转基因小鼠允许解剖动态过程，这些过程导致癌具有不同的转录曲线，这些转录谱类似于女性（包括ER）的腔内肿瘤亚型？表达。 在这一新应用中，我们将采用该模型来研究PRL与卵巢类固醇合作调节乳腺上皮祖细胞和肿瘤细胞亚群的假设，从而促进了腔癌的发展。此外，这些肿瘤包含肿瘤引发细胞，这些细胞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AIM 1中，我们将与卵巢类固醇对PRL和串扰在病变之前的非父母乳腺上皮亚群中的影响，如表面标记和功能性祖细胞测定所定义，并确定这些过程的关键介体。在AIM 2中，我们将确定PRL诱导的ER？+癌的肿瘤引发细胞的特征，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AIM 3中，我们将通过检查正常的乳腺亚群和肿瘤亚型的prl和良好特征的致癌信号之间的相互作用，通过检查串扰对早期病变前，病变和营养瘤的上皮亚群的净影响。 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腔内乳腺癌亚型及其在治疗敏感性中的作用的机制。他们将在PRL诱导的ER？+癌中测试癌症干细胞假设，从而产生一种新的且与生物学相关的范式，以理解这种普遍的肿瘤亚型，从而实现了新型治疗方法的设计。