A novel regulator of breast development

描述（由申请人提供）：乳腺发育对大多数哺乳动物的生存能力和许多人类种群的可持续性至关重要。此外，控制乳腺形态发生的外源性和内源性因素反复参与调节乳腺癌的风险、肿瘤亚型和/或转移进展。因此，确定控制乳腺形态发生的网络对于维持人类发育和发现导致乳腺疾病的其他因素是必要的。我们最近发现了一个具有乳房发育缺陷的新大家庭。在这个家族中，一半的男性和女性都有先天性乳头畸形，女性无法发育乳房。该性状遵循常染色体显性遗传模式，不符合任何先前描述的乳房发育缺陷，并且已被定位到不包含任何已建立的乳房发育基因的单个染色体区域。因此，这个家族为发现控制乳房发育和潜在癌症的新突变/基因提供了一个独特的机会。根据这一建议，将对受影响和未受影响的家庭成员进行深度测序，以确定该家庭中与无胸型分离的特定突变。该基因的组织特异性表达将在小鼠和成人乳腺组织的正常乳腺发育过程中进行评估。最后，我们将开发一种新的基因操纵小鼠模型，其中人类突变已经在小鼠基因组中进行了工程设计。这些小鼠将成为确定已鉴定基因在乳房发育中的功能以及人类突变对该功能的影响的重要资源。一旦完成，这项R21提案将揭示控制乳房形态发生的全新途径，并为未来分析其控制发育和可能的癌症的机制提供必要的工具。

DESCRIPTION (provided by applicant): Mammary gland development is essential for the viability of most mammals and the sustainability of many human populations. In addition, exogenous and intrinsic factors that control mammary morphogenesis have repeatedly been implicated in regulating breast cancer risk, tumor subtype, and/or metastatic progression. Thus, identifying the networks that control mammary morphogenesis is necessary for sustaining human development and discovering additional contributors to breast disease. We have recently identified a novel extended family with a breast developmental defect. Half of all males and females in this family have congenital nipple dysmorphia and females fail to develop breasts. The trait follows an autosomal dominant inheritance pattern, does not correspond to any previously described breast developmental defect, and has been mapped to a single chromosomal region that does not contain any established breast development genes. Thus, this family provides a unique opportunity to discover a novel mutation/gene that controls breast development and potentially cancer. With this proposal, deep sequencing will be performed on affected and unaffected family members to identify the specific mutation in this family that segregates with the amastia phenotype. The tissue specific expression of this gene will then be assessed throughout normal mammary gland development in the mouse and in adult human breast tissue. Lastly, we will develop a novel genetically- manipulated mouse model wherein the human mutation has been engineered in the mouse genome. These mice will be a vital resource for establishing the function of the identified gene in breast development and the impact of the human mutation on that function. Upon completion, this R21 proposal will uncover a completely new pathway controlling breast morphogenesis and generate necessary tools for future analyses of the mechanism(s) by which it controls development and possibly cancer.