Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland.
Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland.
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DOI：
10.1371/journal.pgen.1004323
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发表时间：
2014-05
期刊：
影响因子：
4.5
通讯作者：
Humbert PO
中科院分区：
文献类型：
--
作者：
Godde NJ;Sheridan JM;Smith LK;Pearson HB;Britt KL;Galea RC;Yates LL;Visvader JE;Humbert PO
极性协调细胞运动、分化、增殖和凋亡，以构建和维持复杂的上皮组织，如乳腺。极性丧失和这些过程的失调是恶性进展中的关键事件，但极性丧失如何以及在哪个阶段对乳腺发育和肿瘤发生产生影响尚不清楚。Scrib是一种核心极性调节基因和肿瘤抑制基因，但迄今为止，我们对Scrib在乳腺中功能的了解仅限于细胞培养和细胞系移植研究。利用条件性小鼠模型的Scrib损失，我们报告的第一次，Scrib是必不可少的乳腺导管形态发生，乳腺祖细胞的命运和维护，我们证明了一个关键的和具体的作用，Scribble在控制乳腺癌进展的早期步骤。特别是，Scrib-deficiency显着诱导Fra 1表达和基底祖细胞克隆形成，这导致完全渗透性导管增生的特征是高细胞周转率，MAPK活性亢进，坦率的极性损失与混合的顶端和基底侧膜成分和扩张的非典型管腔细胞。我们还首次显示了在哺乳动物纺锤体取向与乳腺增生的发病与异常的管腔细胞纺锤体取向和失败，在导管tubulogenesis的最后阶段的arrhythmia的作用。将MAPK/Fra 1恢复到基线水平可防止Scrib-hyperplasia，而持续的Scrib-deficiency诱导肺泡增生，并增加乳腺肿瘤的发病率、发病率和分级。这些发现基于确定的遗传小鼠模型，为乳腺导管成熟和稳态提供了基本见解，并揭示了Scrib丢失激活MAPK/Fra 1通路，改变乳腺祖细胞活性，以驱动癌前病变并加速肿瘤进展。极性允许细胞功能的专门化，并且是协调细胞运动、分化、增殖和凋亡以构建和维持复杂组织如乳腺所必需的。极性的破坏是癌症的诊断标准，但核心极性基因的失调如何导致癌症以及在哪个阶段极性丧失促进体内乳腺癌的发展仍然知之甚少。为了直接解决这个问题，我们删除了小鼠乳腺中的核心极性基因Scrib。在成熟但非青春期小鼠中，划痕损失导致组织结构损失和导管增生。细胞增殖的发生与纺锤体方向缺陷、细胞不能正常生长有关，并由高细胞更新率和Ras/Erk/Fra 1 MAPK通路激活维持。Scrib缺乏激活祖细胞并导致非典型管腔细胞的过度生长以及导管和肺泡增生的发展。总体而言，这些小鼠表现出乳腺肿瘤的发生率、发作和分级增加。这些研究提供了一个明确的证明核心极性基因在维持乳腺上皮完整性在体内发挥的关键作用。这种小鼠模型是了解极性在乳腺发育和乳腺癌最初始阶段中的作用的有价值的工具。
Polarity coordinates cell movement, differentiation, proliferation and apoptosis to build and maintain complex epithelial tissues such as the mammary gland. Loss of polarity and the deregulation of these processes are critical events in malignant progression but precisely how and at which stage polarity loss impacts on mammary development and tumourigenesis is unclear. Scrib is a core polarity regulator and tumour suppressor gene however to date our understanding of Scrib function in the mammary gland has been limited to cell culture and transplantation studies of cell lines. Utilizing a conditional mouse model of Scrib loss we report for the first time that Scrib is essential for mammary duct morphogenesis, mammary progenitor cell fate and maintenance, and we demonstrate a critical and specific role for Scribble in the control of the early steps of breast cancer progression. In particular, Scrib-deficiency significantly induced Fra1 expression and basal progenitor clonogenicity, which resulted in fully penetrant ductal hyperplasia characterized by high cell turnover, MAPK hyperactivity, frank polarity loss with mixing of apical and basolateral membrane constituents and expansion of atypical luminal cells. We also show for the first time a role for Scribble in mammalian spindle orientation with the onset of mammary hyperplasia being associated with aberrant luminal cell spindle orientation and a failure to apoptose during the final stage of duct tubulogenesis. Restoring MAPK/Fra1 to baseline levels prevented Scrib-hyperplasia, whereas persistent Scrib deficiency induced alveolar hyperplasia and increased the incidence, onset and grade of mammary tumours. These findings, based on a definitive genetic mouse model provide fundamental insights into mammary duct maturation and homeostasis and reveal that Scrib loss activates a MAPK/Fra1 pathway that alters mammary progenitor activity to drive premalignancy and accelerate tumour progression. Polarity allows the specialization of cell function and is required to coordinate cell movements, differentiation, proliferation and apoptosis to build and maintain complex tissues such as the mammary gland. Disruption of polarity is a diagnostic criterion of cancer, but exactly how deregulation of core polarity genes contribute to cancer and at which stage polarity loss promotes breast cancer development in vivo is still poorly understood. To address this directly, we deleted the core polarity gene Scrib specifically in the mouse mammary gland. Scrib loss resulted in loss of tissue architecture and duct hyperplasia in mature but not pubescent mice. Onset of hyperplasia was associated with defective spindle orientations, a failure to apoptose and was sustained by high cell turnover and Ras/Erk/Fra1 MAPK pathway activation. Scrib deficiency activated progenitors and resulted in the excess growth of atypical luminal cells and the development of ductal and alveolar hyperplasia. Overall these mice exhibited an increased incidence, onset and grade of mammary tumours. These studies provide a definitive demonstration of the critical role played by core polarity genes in maintaining mammary epithelial integrity in vivo. This mouse model is a valuable tool for understanding the role of polarity in mammary development and the most initial stages of breast cancer.
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影响因子：
3.8
作者：
Chiappetta, Gennaro;Ferraro, Angelo;Botti, Gerardo;Monaco, Mario;Pasquinelli, Rosa;Vuttariello, Emilia;Arnaldi, Liliane;Di Bonito, Maurizio;D'Aiuto, Giuseppe;Pierantoni, Giovanna Maria;Fusco, Alfredo
通讯作者：
Fusco, Alfredo
影响因子：
8
作者：
Andrechek, ER;White, D;Muller, WJ
通讯作者：
Muller, WJ
影响因子：
8
作者：
Belguise, K;Kersual, N;Chalbos, D
通讯作者：
Chalbos, D
影响因子：
23.9
作者：
Bouras, Toula;Pal, Bhupinder;Visvader, Jane E.
通讯作者：
Visvader, Jane E.
影响因子：
9.2
作者：
Audebert, S;Navarro, C;Borg, JP
通讯作者：
Borg, JP