Prolactin: mammary progenitors and tumor initiating cells in luminal carcinomas

描述(申请人提供)：75%的女性乳腺肿瘤表达雌激素受体α(ER？+)。尽管抗雌激素显著降低了许多患有这种“管腔”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抗药性癌症。肿瘤起始细胞，或“癌症干细胞”，已被认为与传统疗法的耐药、复发和转移有关。然而，腔内肿瘤的起源和抵抗治疗的细胞的特征仍然未知。能够促进这些研究的ER？+乳腺癌小鼠模型非常罕见。多项研究表明，催乳素(PRL)与ER？+乳腺癌的发病机制和治疗反应密切相关。我们的体内模型，NRL-PRL转基因小鼠，允许解剖导致多种癌症的动态过程，其转录谱类似于女性的腔内肿瘤亚型，包括ER？表情。 在这一新的应用中，我们将利用这一模型来研究PRL与卵巢类固醇激素协同调节乳腺上皮祖细胞和肿瘤细胞亚群的假设，促进管腔癌的发展。此外，这些肿瘤含有肿瘤起始细胞，它们表现出与大多数肿瘤细胞不同的激素依赖性和治疗敏感性。在目标1中，我们将确定PRL和卵巢类固醇的串扰对病变前未分娩女性乳腺上皮细胞亚群的影响，通过表面标志物和功能前体分析来定义，并确定这些过程的关键调节因子。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，我们将通过检测在病变前、早期病变和癌组织中串扰对上皮亚群的净影响，阐明PRL和一个特征良好的致癌信号--连环蛋白在调节正常乳腺亚群和肿瘤亚型中的相互作用。 这些研究将阐明催乳素与内源性类固醇和癌基因相互作用促进管腔性乳腺癌亚型的机制(S)，以及它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，为理解这一流行的肿瘤亚型产生一个新的生物学相关范式，使设计新的治疗方法成为可能。 公共卫生相关性：尽管抗雌激素显著降低了许多患有“腔内”ER+型乳腺癌的女性的死亡率，但这些患者中有四分之一最终死于这些肿瘤。“癌症干细胞”被认为与传统疗法的耐药、复发和转移有关。然而，腔内肿瘤的起源和抵抗治疗的细胞的特征仍然未知。我们将使用ER+乳腺癌的小鼠模型来阐明促进这一乳腺癌亚型的激素-癌基因相互作用，并在ER+乳腺癌中测试癌症干细胞假说。这些研究将产生一个新的和生物学相关的范例来理解这种流行的肿瘤亚型，并使新的治疗方法的设计成为可能。

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. PUBLIC HEALTH RELEVANCE: Although anti-estrogens have markedly reduced mortality for many women with the "luminal" ER+ type of breast cancer, one quarter of these patients eventually succumb to these tumors. "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. We will use a mouse model of ER+ breast cancer to elucidate hormone-oncogene interactions which promote this breast cancer subtype, and to test the cancer stem cell hypothesis in ER+ carcinomas. These studies will generate a new and biologically relevant paradigm for understanding this prevalent tumor subtype, and enable the design of novel therapeutic approaches.