Mammary epithelial cell transformation: insights from cell culture and mouse models.
Mammary epithelial cell transformation: insights from cell culture and mouse models.
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乳腺上皮细胞转化：细胞培养和小鼠模型的见解。
DOI：
10.1186/bcr1275
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发表时间：
2005
影响因子：
7.4
通讯作者：
Band, V
中科院分区：
文献类型：
--
作者：
Dimri, G;Band, H;Band, V
正常人乳腺上皮细胞（HMEC）具有有限的寿命，并且在培养中不经历自发永生化。致癌转化的关键是细胞克服衰老检查点的能力，这些检查点定义了它们的复制寿命，并无限繁殖-这种现象称为永生化。HMEC可以通过将其暴露于化学物质或辐射，或使其过度表达某些细胞基因或病毒癌基因而永生。然而，HMEC永生化的最有效和可重复的模型仍然是高危人乳头瘤病毒（HPV）癌基因E6和E7的表达。细胞培养模型已经确定了肿瘤抑制蛋白（pRb和p53）、细胞周期蛋白依赖性激酶（p16 INK 4a、p21、p27和p57）抑制剂、p14 ARF、端粒酶和小G蛋白Rap、Rho和Ras在HMEC永生化和转化中的作用。这些细胞培养模型也提供了证据表明，在正常乳腺组织中存在多种上皮细胞亚型，具有不同的致癌易感性模式。再加上来自原发性乳腺癌不同分子画像的信息，这些发现表明乳腺细胞的各种亚型可能是不同亚型乳腺癌的前体。培养物中HMEC的完全致癌转化需要多种基因产物的表达，例如SV 40大T和小t、hTERT（人端粒酶的催化亚基）、Raf、磷脂酰肌醇3-激酶和Ral-GEF（Ral鸟嘌呤核苷酸交换因子）。然而，当植入裸鼠时，这些转化的细胞通常产生低分化癌而不是腺癌。另一方面，使用ErbB 2/neu、Ras、Myc、SV 40 T或多瘤病毒T的转基因小鼠模型发展腺癌，提高了亲本正常细胞亚型可能决定乳腺肿瘤病理类型的可能性。三维模型和乳腺球模型的可用性已经导致了推定干细胞的鉴定，但需要更多的研究来确定它们作为不同乳腺癌前体细胞的生物学作用和潜力。在细胞培养和小鼠模型中结合使用转化策略以及人类乳腺癌亚型的分子定义应有助于阐明乳腺癌多样性的本质并开发个体化治疗。
Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely – a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16INK4a, p21, p27 and p57), p14ARF, telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies.
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影响因子：
50.3
作者：
Crawford, YG;Gauthier, ML;Tlsty, TD
通讯作者：
Tlsty, TD
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
10.5
作者：
Gudjonsson, T;Villadsen, R;Petersen, OW
通讯作者：
Petersen, OW
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
15.9
作者：
Ben-Porath, I;Weinberg, RA
通讯作者：
Weinberg, RA