The role of membrane mucin MUC4 in breast cancer metastasis.
The role of membrane mucin MUC4 in breast cancer metastasis.
复制标题
DOI：
10.1530/erc-21-0083
复制
发表时间：
2021-11-24
影响因子：
3.9
通讯作者：
Carraway KL
中科院分区：
文献类型：
--
作者：
Dreyer CA;VanderVorst K;Free S;Rowson-Hodel A;Carraway KL
出现远处转移的主要障碍是循环肿瘤细胞（CTC）在脉管系统内的存活。致死性应激源包括来自血流的剪切力、由细胞脱离引起的失巢凋亡和暴露于自然杀伤细胞，这些因素结合联合收割机以破坏原发性肿瘤细胞存活的能力并最终导致远处病变。通过治疗性干预进一步减弱这种限速过程为改善癌症患者的预后提供了非常有吸引力的机会，从而促使人们需要更深入地了解CTC活力的分子和细胞机制。MUC4是在多种组织的上皮细胞的顶端表面表达的非常大且高度糖基化的蛋白质，其参与细胞生长信号传导和增殖，并且有助于细胞衬里的保护和润滑。对患者匹配的乳腺肿瘤标本的分析表明，在所有乳腺肿瘤亚型中，MUC4蛋白水平在转移性病变中相对于原发性肿瘤上调，这表明MUC4过表达在转移中可能具有选择性优势。对HER2阳性乳腺癌的基因工程小鼠模型的分析已经证明，MUC4缺失显著抑制了转移效率，并且MUC4敲除的肿瘤细胞与已知支持CTC活力的血小板和白色血细胞的结合较差。在这篇综述中，我们讨论了MUC4在肿瘤进展和转移中的不同作用，并提出干预MUC4与血源性聚集细胞上的结合伙伴的细胞间相互作用可能会阻碍乳腺癌的转移效率。
A major barrier to the emergence of distant metastases is the survival of circulating tumor cells (CTCs) within the vasculature. Lethal stressors including shear forces from blood flow, anoikis arising from cellular detachment, and exposure to natural killer cells, combine to subvert the ability of primary tumor cells to survive and ultimately seed distant lesions. Further attenuation of this rate-limiting process via therapeutic intervention offers a very attractive opportunity for improving cancer patient outcomes, in turn prompting the need for a deeper understanding of the molecular and cellular mechanisms underlying CTC viability. MUC4 is a very large and heavily glycosylated protein expressed at the apical surfaces of the epithelia of a variety of tissues, is involved in cellular growth signaling and adhesiveness, and contributes to the protection and lubrication of cellular linings. Analysis of patient-matched breast tumor specimens has demonstrated that MUC4 protein levels are upregulated in metastatic lesions relative to primary tumor among all breast tumor subtypes, pointing to a possible selective advantage for MUC4 overexpression in metastasis. Analysis of a genetically engineered mouse model of HER2-positive breast cancer has demonstrated that metastatic efficiency is markedly suppressed with MUC4 deletion, and MUC4-knockout tumor cells poorly associate with platelets and white blood cells known to support CTC viability. In this review we discuss the diverse roles of MUC4 in tumor progression and metastasis, and propose that intervening in MUC4 intercellular interactions with binding partners on blood-borne aggregating cells could potentially thwart breast cancer metastatic efficiency.
通过蛋白体降解对膜粘蛋白MUC4的TGFBETA调节。
影响因子：
4
作者：
Lomako, Wieslawa M.;Lomako, Joseph.;Soto, Pedro;Carraway, Coralie A. Carothers;Carraway, Kermit L.
通讯作者：
Carraway, Kermit L.