Lindley Linsey E, Curtis Kevin M, Sanchez-Mejias Avencia, Rieger Megan E, Robbins David J, Briegel Karoline J
Department of Biochemistry and Molecular Biology, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine and Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33136, USA.
Development. 2015 Mar 1;142(5):893-904. doi: 10.1242/dev.110403. Epub 2015 Feb 5.
The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin(-)CD29(high)CD24(+) basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis.
多能乳腺干细胞（MaSCs）的鉴定为乳腺在成年期独特的再生能力提供了解释。然而，目前尚不清楚哪些基因维持MaSCs并控制它们分化为两种上皮谱系，即管腔上皮谱系和基底上皮谱系。LBH是WNT信号通路中的一种新型转录辅因子，其生理功能迄今未知。LBH在乳腺发育过程中表达，并在侵袭性“基底”亚型乳腺癌中异常过表达。在此，我们探讨了LBH在乳腺生成中的体内作用。我们发现，在出生后的乳腺上皮中，LBH主要表达于Lin(-)CD29(high)CD24(+)基底MaSC群体中。LBH条件性失活后，小鼠在青春期和妊娠期乳腺组织扩张出现明显延迟，同时管腔上皮分化增加，而基底谱系分化受到抑制。这些缺陷可追溯到基底MaSCs的频率及其自我更新/分化潜能的严重降低。从机制上讲，LBH诱导关键上皮干细胞转录因子ΔNp63的表达，以促进基底MaSC状态并抑制管腔上皮分化基因，主要是编码雌激素受体α（Esr1/ERα）的基因。总的来说，这些研究确定LBH是基底MaSC扩增/维持的关键调节因子，这对其在乳腺癌发病机制中的潜在作用具有重要意义。
