Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium.
Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium.
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DOI：
10.1371/journal.pone.0119718
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Stein T
中科院分区：
文献类型：
--
作者：
Iglesias JM;Cairney CJ;Ferrier RK;McDonald L;Soady K;Kendrick H;Pringle MA;Morgan RO;Martin F;Smalley MJ;Blyth K;Stein T
我们以前已经表明，膜联蛋白A8（ANXA 8）与乳腺癌的基底细胞样亚群（包括BRCA 1相关乳腺癌）和预后不良密切相关;而在小鼠乳腺中，AnxA 8 mRNA在低增殖性的离体青春期小鼠乳腺导管上皮和强制复旧后表达，但在离体高增殖性终末芽（TEB）或妊娠期间不表达。为了更好地了解ANXA 8与该乳腺癌亚组的相关性，我们确定了ANXA 8在乳腺中的细胞分布以及ANXA 8对细胞增殖的影响。我们发现，ANXA 8在小鼠乳腺中的表达是强大的青春期前的扩展之前的基本导管网络，并限于一个独特的亚群的导管腔上皮细胞，但没有检测到在TEB或在怀孕期间的肺泡。同样，在退化后期，其表达被发现在幸存的导管上皮，但不是在凋亡的肺泡。双重免疫荧光（IF）显示，ANXA 8阳性（+ve）细胞是ER-α阴性（−ve），大多数是静止的，定义为青春期和妊娠中期缺乏Ki 67表达，但未终末分化，约15%的ANXA 8 +ve细胞在妊娠开始时（第4.5天）重新进入细胞周期。对来自FACS分选的细胞和双IF的RNA的RT-PCR显示，ANXA 8 +ve细胞是c-kit +ve管腔祖细胞的亚群，其最近被鉴定为基底样乳腺癌的起源细胞。ANXA 8在乳腺上皮细胞系Kim-2中的过表达导致G 0/G1停滞并抑制Ki 67表达，表明细胞周期退出。因此，我们的数据确定ANXA 8是正常小鼠乳腺导管上皮细胞中潜在的静止介质，而其在基底样乳腺癌中的表达可能与ANXA 8与其特定起源细胞的相关性有关。
We have previously shown that Annexin A8 (ANXA8) is strongly associated with the basal-like subgroup of breast cancers, including BRCA1-associated breast cancers, and poor prognosis; while in the mouse mammary gland AnxA8 mRNA is expressed in low-proliferative isolated pubertal mouse mammary ductal epithelium and after enforced involution, but not in isolated highly proliferative terminal end buds (TEB) or during pregnancy. To better understand ANXA8’s association with this breast cancer subgroup we established ANXA8’s cellular distribution in the mammary gland and ANXA8’s effect on cell proliferation. We show that ANXA8 expression in the mouse mammary gland was strong during pre-puberty before the expansion of the rudimentary ductal network and was limited to a distinct subpopulation of ductal luminal epithelial cells but was not detected in TEB or in alveoli during pregnancy. Similarly, during late involution its expression was found in the surviving ductal epithelium, but not in the apoptotic alveoli. Double-immunofluorescence (IF) showed that ANXA8 positive (+ve) cells were ER-alpha negative (−ve) and mostly quiescent, as defined by lack of Ki67 expression during puberty and mid-pregnancy, but not terminally differentiated with ∼15% of ANXA8 +ve cells re-entering the cell cycle at the start of pregnancy (day 4.5). RT-PCR on RNA from FACS-sorted cells and double-IF showed that ANXA8+ve cells were a subpopulation of c-kit +ve luminal progenitor cells, which have recently been identified as the cells of origin of basal-like breast cancers. Over expression of ANXA8 in the mammary epithelial cell line Kim-2 led to a G0/G1 arrest and suppressed Ki67 expression, indicating cell cycle exit. Our data therefore identify ANXA8 as a potential mediator of quiescence in the normal mouse mammary ductal epithelium, while its expression in basal-like breast cancers may be linked to ANXA8’s association with their specific cells of origin.
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影响因子：
1.8
作者：
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通讯作者：
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