CAP CELL DERIVED TUMORS--MODEL OF INVASIVE BREAST CANCER

乳腺癌治疗中的一个主要问题和死亡率的主要原因是原发性乳腺肿瘤的侵袭和转移。关于乳腺肿瘤的基本生物学知之甚少，这可以解释为什么某些肿瘤在某些个体中具有侵袭性，而在另一些个体中相对静止。 肿瘤产生的细胞类型可能决定其侵袭和转移的潜力。 乳腺由不同类型的细胞组成，包括帽细胞;一种分化程度较低、高度增殖的细胞，位于小鼠乳腺的末端芽（TEB）。 TEBs侵入青春期腺体的脂肪间质，建立导管网络。 据报道，这些专门的结构是致癌物诱导的DNA损伤的目标。 它们在人类中的对应物被称为小叶内导管，也是癌性病变的部位。 我们假设TEB帽细胞群特异性的遗传变化将导致侵袭性肿瘤和转移性疾病。 这项研究的长期目标是了解为什么一些乳腺肿瘤是良性的，而另一些是转移性的，并将这些信息转化为更好的治疗方案。P-钙粘蛋白通常在TEB及其祖细胞的帽细胞中表达。 最近的研究发现，P-钙粘蛋白在人类乳腺肿瘤中的表达与患者生存率低密切相关，这提出了两种可能的解释。 在通常不表达P-钙粘蛋白的转化上皮细胞中P-钙粘蛋白表达上调，或者这些高度侵袭性肿瘤起源于帽细胞或干细胞样祖细胞。本提案中概述的实验将直接研究后一种可能性。 为了确定特定乳腺细胞亚群在肿瘤发生中的作用，我们将产生一个诱导型表达系统，其中转基因表达可以在体内受到严格调控。 内源性P-钙粘蛋白启动子将用于指导帽细胞的表达。 在乳腺发育的特定时期，通过给予四环素衍生物多西环素，将在帽细胞中诱导neu/HER-2原癌基因。将在这些动物中检查肿瘤发展，并将肿瘤病理学与人乳腺肿瘤以及转基因模型进行比较。 这项研究的目的是确定高度增殖和侵袭性帽细胞群是否是转移性乳腺癌的靶点。

A major problem in breast cancer treatment and the leading cause of mortality is invasion and metastasis of primary breast tumors. Very little is known about the fundamental biology of mammary tumors that can explain why certain tumors are aggressive in some individuals while relatively quiescent in others. The cell type from which the tumor arises may dictate its potential for invasion and metastasis. The mammary gland consists of different cell types including the cap cell; a less differentiated, highly proliferative cell basally located in the terminal end bud (TEB) of the murine mammary gland. The TEBs invade the fatty stroma of the pubertal gland establishing the ductal network. These specialized structures are reported to be targets for carcinogen- induced DNA damage. Their human counterparts are called intralobular ducts and are also sites of cancerous lesions. We hypothesize that genetic change specific to the cap cell population of the TEB will lead to aggressive tumors and metastatic disease. The long term goal of this research is to understand why some breast tumors are benign and others metastatic, and translate this information into better treatment protocols. P-cadherin is normally expressed in the cap cells of the TEB and its progenitors. The recent finding that P-cadherin expression in human breast tumors strongly correlates with poor patient survival suggests two possible explanations. Either P-cadherin expression is upregulated in transformed epithelial cells which normally do not express P-cadherin or these highly invasive tumors originate from a cap cell or stem cell-like progenitor. The experiments outlined in this proposal will directly examine the latter possibility. In order to determine the role of a specific subset of mammary cells in tumorigenesis we will generate an inducible expression system in which transgene expression can be tightly regulated in vivo. The endogenous P- cadherin promoter will be used to direct expression to the cap cells. The neu/HER-2 proto-oncogene will be induced in cap cells during specific periods of mammary gland development by administration of the tetracycline derivative, doxycycline. Tumor development will be examined in these animals and tumor pathology will be compared to human breast tumors as well as transgenic models. The goal of this research is to determine whether the highly proliferative and invasive cap cell population is a target for metastatic breast cancer.