Coletta Ricardo D, McCoy Erica L, Burns Valerie, Kawakami Kiyoshi, McManaman James L, Wysolmerski John J, Ford Heide L
Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, 12800 E, 19th Ave, Aurora, CO 80045, USA.
BMC Dev Biol. 2010 Jan 14;10:4. doi: 10.1186/1471-213X-10-4.
The Six1 homeobox gene is highly expressed in the embryonic mammary gland, continues to be expressed in early postnatal mammary development, but is lost when the mammary gland differentiates during pregnancy. However, Six1 is re-expressed in breast cancers, suggesting that its re-instatement in the adult mammary gland may contribute to breast tumorigenesis via initiating a developmental process out of context. Indeed, recent studies demonstrate that Six1 overexpression in the adult mouse mammary gland is sufficient for initiating invasive carcinomas, and that its overexpression in xenograft models of mammary cancer leads to metastasis. These data demonstrate that Six1 is causally involved in both breast tumorigenesis and metastasis, thus raising the possibility that it may be a viable therapeutic target. However, because Six1 is highly expressed in the developing mammary gland, and because it has been implicated in the expansion of mammary stem cells, targeting Six1 as an anti-cancer therapy may have unwanted side effects in the breast.
We sought to determine the role of Six1 in mammary development using two independent mouse models. To study the effect of Six1 loss in early mammary development when Six1 is normally expressed, Six1-/- embryonic mammary glands were transplanted into Rag1-/- mice. In addition, to determine whether Six1 downregulation is required during later stages of development to allow for proper differentiation, we overexpressed Six1 during adulthood using an inducible, mammary-specific transgenic mouse model. Morphogenesis of the mammary gland occurred normally in animals transplanted with Six1-/- embryonic mammary glands, likely through the redundant functions of other Six family members such as Six2 and Six4, whose expression was increased in response to Six1 loss. Surprisingly, inappropriate expression of Six1 in the adult mammary gland, when levels are normally low to absent, did not inhibit normal mammary differentiation during pregnancy or lactation.
Six1 is not critical for normal mammary gland development, since neither loss nor inappropriate overexpression of Six1 adversely affects normal mammary gland development or function. However, as both Six2 and Six4 levels are increased in Six1-/- mammary glands, we postulate that these Six family members are functionally redundant in the gland, as is true of many homeobox gene families. This data, in conjunction with recent findings that Six1 is capable of promoting breast cancer initiation and progression, suggest that Six1 may serve as a reasonable chemotherapeutic target in a clinical setting, particularly for those women diagnosed with breast cancer in their childbearing years.
Six1 同源框基因在胚胎期乳腺中高度表达，在出生后早期乳腺发育过程中持续表达，但在孕期乳腺分化时表达消失。然而，Six1 在乳腺癌中重新表达，这表明其在成年乳腺中的重新激活可能通过启动异常的发育过程促进乳腺肿瘤发生。事实上，最近的研究表明，在成年小鼠乳腺中过表达 Six1 足以引发浸润性癌，并且在乳腺癌异种移植模型中过表达 Six1 会导致转移。这些数据表明 Six1 与乳腺肿瘤发生和转移均存在因果关系，因此增加了其可能成为可行治疗靶点的可能性。然而，由于 Six1 在发育中的乳腺中高度表达，并且其与乳腺干细胞的扩增有关，将 Six1 作为抗癌疗法可能会对乳腺产生不良副作用。
我们试图使用两种独立的小鼠模型来确定 Six1 在乳腺发育中的作用。为了研究 Six1 在正常表达时缺失对早期乳腺发育的影响，将 Six1-/-胚胎乳腺移植到 Rag1-/-小鼠体内。此外，为了确定在发育后期是否需要下调 Six1 以实现正常分化，我们使用可诱导的乳腺特异性转基因小鼠模型在成年期过表达 Six1。移植 Six1-/-胚胎乳腺的动物乳腺形态发生正常，这可能是由于其他 Six 家族成员（如 Six2 和 Six4）的冗余功能，它们的表达因 Six1 的缺失而增加。令人惊讶的是，当成年乳腺中 Six1 水平通常很低或不存在时，其不适当表达并未抑制孕期或哺乳期的正常乳腺分化。
Six1 对正常乳腺发育并不关键，因为 Six1 的缺失或不适当过表达均未对正常乳腺发育或功能产生不利影响。然而，由于 Six1-/-乳腺中 Six2 和 Six4 的水平均升高，我们推测这些 Six 家族成员在乳腺中具有功能冗余性，许多同源框基因家族都是如此。这些数据，结合最近关于 Six1 能够促进乳腺癌起始和进展的发现，表明 Six1 在临床环境中可能是一个合理的化疗靶点，特别是对于那些在育龄期被诊断为乳腺癌的女性。
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