Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation carriers.
Altered proliferation and differentiation properties of primary mammary epithelial cells from BRCA1 mutation carriers.
复制标题
DOI：
10.1158/0008-5472.can-08-2954
复制
发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Wulf GM
中科院分区：
文献类型：
--
作者：
Burga LN;Tung NM;Troyan SL;Bostina M;Konstantinopoulos PA;Fountzilas H;Spentzos D;Miron A;Yassin YA;Lee BT;Wulf GM
女性BRCA1突变携带者在其一生中患乳腺癌的概率接近80%。我们假设BRCA1突变携带者中处于危险的乳腺上皮含有增殖和分化特性改变的乳腺上皮细胞（MEC）。利用三维培养技术在体外培养MEC，我们发现形成集落的能力（克隆性的一种指示）仅限于MEC中的醛脱氢酶1阳性部分，而在HCC1937 BRCA1突变癌细胞中则不然。来自BRCA1突变携带者（n = 9）的原代MEC与正常对照（n = 6；P = 0.006）相比，克隆生长能力高28%，并且它们的集落明显更大。对照和BRCA1突变携带者的集落通过免疫组织化学检测BRCA1呈阳性，并且来自BRCA1携带者的79%的检测单集落保留了BRCA1的杂合性（相对杂合度，ROH）。来自BRCA1突变携带者的集落经常显示高表皮生长因子受体（EGFR）表达（71%为EGFR阳性，而对照中为44%），并且雌激素受体（ERα）呈阴性（32%为ER阴性，44%为混合，24%为ER阳性，而对照中90%为ER阳性）。CK14和p63的表达没有显著差异。微阵列研究显示，来自BRCA1突变的原代乳腺上皮细胞（PMEC）的集落呈现出在BRCA1相关肿瘤中发现的表达谱，并且EGFR通路被上调。我们得出结论，BRCA1单倍体不足导致BRCA1突变携带者的PMEC克隆生长和增殖能力增加，可能是由于EGFR通路激活的结果。这些改变的生长和分化特性可能使BRCA1突变的PMEC容易发生转化，并易患雌激素受体阴性、表皮生长因子受体阳性的乳腺癌。
Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MEC) with altered proliferation and differentiation properties. Using a three-dimensional culture technique to grow MECs ex vivo, we found that the ability to form colonies, an indication of clonality, was restricted to the aldehyde dehydrogenase 1–positive fraction in MECs but not in HCC1937 BRCA1-mutant cancer cells. Primary MECs from BRCA1 mutation carriers (n = 9) had a 28% greater ability for clonal growth compared with normal controls (n= 6; P = 0.006), and their colonies were significantly larger. Colonies in controls and BRCA1 mutation carriers stained positive for BRCA1 by immunohistochemistry, and 79% of the examined single colonies from BRCA1 carriers retained heterozygosity for BRCA1 (ROH). Colonies from BRCA1 mutation carriers frequently showed high epidermal growth factor receptor (EGFR) expression (71% EGFR positive versus 44% in controls) and were negative for estrogen receptor (ERα; 32% ER negative, 44% mixed, 24% ER positive versus 90% ER positive in controls). Expression of CK14 and p63 were not significantly different. Microarray studies revealed that colonies from BRCA1-mutant PMECs anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is up-regulated. We conclude that BRCA1 haploin-sufficiency leads to an increased ability for clonal growth and proliferation in the PMECs of BRCA1 mutation carriers, possibly as a result of EGFR pathway activation. These altered growth and differentiation properties may render BRCA1-mutant PMECs vulnerable to transformation and predispose to the development of ER-negative, EGFR-positive breast cancers.