Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway.
Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway.
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小鼠乳腺中Kindlin-2的靶向缺失抑制TGF-β/EGF致癌信号通路下游的肿瘤生长、侵袭和转移。
DOI：
10.3390/cancers14030639
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发表时间：
2022-01-27
期刊：
影响因子：
5.2
通讯作者：
Sossey-Alaoui K
中科院分区：
文献类型：
--
作者：
Wang W;Rana PS;Alkrekshi A;Bialkowska K;Markovic V;Schiemann WP;Plow EF;Pluskota E;Sossey-Alaoui K
我们和其他人的研究已经证实，在乳腺癌（BC）中，癌细胞中表达的kindin -2是肿瘤进展和转移的主要驱动因素。然而，在乳腺（肿瘤微环境）中表达的Kindlin-2在BC发病中的作用尚未被研究。为此，我们在小鼠乳腺基底细胞中产生了一种特异性缺乏Kindlin-2表达的小鼠品系。当这些Kindlin-2缺失的小鼠用乳腺脂肪垫注射癌细胞攻击时，Kindlin-2缺失的乳腺隔室中Kindlin-2的缺失虽然对小鼠的发育没有影响，但却显著抑制了BC肿瘤的生长和转移。在分子信号水平上，我们发现Kindlin-2在TGF-β/EGF信号轴下游的癌细胞和肿瘤微环境（乳腺上皮细胞）中都起着重要的调节BC进展和转移的作用。乳腺癌（BC）是癌症相关死亡的主要原因之一，部分原因是其侵袭性和转移性。kindin -2 （FERMT2）与几种癌症的发病机制有关。虽然Kindlin-2在调节BC的侵袭-转移级联反应中的作用已被广泛报道，但其在BC的发生和进展中的功能仍有待充分阐明。因此，我们以Fermt2 （K2lox/lox）位点为靶点，通过将K2lox/lox小鼠与K14-Cre小鼠杂交，在乳腺肌上皮腔室中组织特异性地缺失Kindlin-2，从而产生了一种floxed小鼠品系。在缺失Kindlin-2的小鼠中，乳腺上皮细胞（MECs）中Kindlin-2的缺失对乳腺发育、生育和泌乳没有有害影响。然而，在乳腺癌的同基因小鼠模型中，特异性敲除Kindlin-2抑制了接种到乳腺脂肪垫的小鼠E0771 BC细胞的生长和转移。然而，将E0771细胞注射到Kindlin-2缺失小鼠的侧尾静脉中，对肿瘤在肺部的定植没有影响，从而确立了MEC Kindlin-2在支持BC肿瘤生长和转移中的关键作用。在机制上，我们发现MEC kindlin -2介导的肿瘤生长和转移抑制是通过调节TGF-β/ERK MAP激酶信号轴来完成的。因此，乳腺微环境中的Kindlin-2促进了BC的进展和转移。
Studies from our group and others have established Kindlin-2 that is expressed in the cancer cells as a major driver of tumor progression and metastasis in breast cancer (BC). The role of Kindlin-2 that is expressed in the mammary glands (tumor microenvironment) in the pathogenesis of BC has, however, not been investigated. To this end, we generated a mouse strain that specifically lacks expression of Kindlin-2 in the basal cells within the mouse mammary glands. Loss of Kindlin-2 in this mammary gland compartment, while having no effect on mouse development, significantly inhibited BC tumors growth and metastasis when these Kindlin-2-deficient mice were challenged with mammary fat pad injection of cancer cells. At the molecular signaling level, we found that Kindlin-2 plays a significant role in regulating BC progression and metastasis in both the cancer cells and the tumor microenvironment (mammary epithelial cells) downstream of a TGF-β/EGF signaling axis. Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2lox/lox) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2lox/lox mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC.
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影响因子：
6
作者：
Godbout E;Son DO;Hume S;Boo S;Sarrazy V;Clément S;Kapus A;Wehrle-Haller B;Bruckner-Tuderman L;Has C;Hinz B
通讯作者：
Hinz B
影响因子：
21.1
作者：
Liu, Yan;Zhu, Yun;Zhang, Rongguang
通讯作者：
Zhang, Rongguang
影响因子：
82.9
作者：
Malinin, Nikolay L.;Zhang, Li;Byzova, Tatiana V.
通讯作者：
Byzova, Tatiana V.
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ
影响因子：
20.3
作者：
Pluskota, Elzbieta;Ma, Yi;Plow, Edward F.
通讯作者：
Plow, Edward F.