Prolactin: mammary progenitors and tumor initiating cells in luminal carcinomas

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?+)。尽管抗雌激素显著降低了许多患有这种“腔内”肿瘤亚型的妇女的死亡率，但这些患者中有四分之一最终死于抗雌激素抵抗性癌症。肿瘤起始细胞或“癌症干细胞”与常规治疗的耐药、复发和转移有关。然而，腔内肿瘤的起源和无法治疗的细胞的特征仍然未知。小鼠ER模型能促进这些研究的乳腺癌非常罕见。多项研究表明，催乳素（PRL）与ER的发病机制和治疗反应性密切相关。+乳腺癌。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？表达式。

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.