The miR-200 family consists of five members expressed as two clusters: miR-200c/141 cluster and miR-200b/200a/429 cluster. In the mammary gland, miR-200s maintain epithelial identity by decreasing the expression of mesenchymal markers leading to high expression of epithelial markers. While the loss of miR-200s is associated with breast cancer growth and metastasis the impact of miR-200 expression on mammary tumor initiation has not been investigated. Using mammary specific expression of the miR-200b/200a/429 cluster in transgenic mice, we found that elevated expression miR-200s could almost completely prevent mammary tumor development. Only 1 of 16 MTB-IGFIRba429 transgenic mice (expressing both the IGF-IR and miR-200b/200a/429 transgenes) developed a mammary tumor while 100% of MTB-IGFIR transgenic mice (expressing only the IGF-IR transgene) developed mammary tumors. RNA sequencing, qRT-PCR, and immunohistochemistry of mammary tissue from 55-day old mice found Spp1, Saa1, and Saa2 to be elevated in mammary tumors and inhibited by miR-200b/200a/429 overexpression. This study suggests that miR-200s could be used as a preventative strategy to protect women from developing breast cancer. One concern with this approach is the potential negative impact miR-200 overexpression may have on mammary function. However, transgenic overexpression of miR-200s, on their own, did not significantly impact mammary ductal development indicating the miR-200 overexpression should not significantly impact mammary function. Thus, this study provides the initial foundation for using miR-200s for breast cancer prevention and additional studies should be performed to identify strategies for increasing mammary miR-200 expression and determine whether miR-200s can prevent mammary tumor initiation by other genetic alterations.

miR-200家族由五个成员组成，表达为两个簇：miR-200c/141簇和miR-200b/200a/429簇。在乳腺中，miR-200 通过降低间充质标志物的表达从而导致上皮标志物的高表达来维持上皮身份。虽然 miR-200 的缺失与乳腺癌生长和转移相关，但 miR-200 表达对乳腺肿瘤发生的影响尚未得到研究。利用转基因小鼠中 miR-200b/200a/429 簇的乳腺特异性表达，我们发现 miR-200s 表达升高几乎可以完全阻止乳腺肿瘤的发展。 16 只 MTB-IGFIRba429 转基因小鼠（同时表达 IGF-IR 和 miR-200b/200a/429 转基因）中只有 1 只产生乳腺肿瘤，而 100% 的 MTB-IGFIR 转基因小鼠（仅表达 IGF-IR 转基因）产生乳腺肿瘤肿瘤。对 55 日龄小鼠乳腺组织进行的 RNA 测序、qRT-PCR 和免疫组织化学发现，Spp1、Saa1和Saa2在乳腺肿瘤中升高，并受到 miR-200b/200a/429 过表达的抑制。这项研究表明 miR-200 可以作为一种预防策略来保护女性免受乳腺癌的侵害。这种方法的一个问题是 miR-200 过度表达可能对乳腺功能产生潜在的负面影响。然而，miR-200 的转基因过表达本身并没有显着影响乳腺导管发育，表明 miR-200 过表达不应显着影响乳腺功能。 因此，这项研究为使用 miR-200 预防乳腺癌提供了初步基础，并且应该进行额外的研究来确定增加乳腺 miR-200 表达的策略，并确定 miR-200 是否可以通过其他基因改变来预防乳腺肿瘤的发生。