During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein.
During hormone depletion or tamoxifen treatment of breast cancer cells the estrogen receptor apoprotein supports cell cycling through the retinoic acid receptor α1 apoprotein.
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在乳腺癌细胞的激素耗竭或他莫昔芬治疗期间，雌激素受体载蛋白支持通过视黄酸受体α1顶蛋白循环的细胞循环。
DOI：
10.1186/bcr2827
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发表时间：
2011-02-07
期刊：
影响因子：
--
通讯作者：
Ratnam M
中科院分区：
文献类型：
--
作者：
Salazar MD;Ratnam M;Patki M;Kisovic I;Trumbly R;Iman M;Ratnam M
目前用于乳腺癌的激素辅助疗法，包括他莫昔芬治疗和雌激素耗竭，总体上是抑制肿瘤的，并且受到肿瘤频繁复发的严重限制。无论耐药机制如何，耐药肿瘤的发展和进展需要在治疗期间持续存在基础水平的循环细胞，其根本原因尚不清楚。在雌激素敏感性乳腺癌细胞中，通过检查细胞生长和周期、细胞凋亡、各种mRNA和蛋白质表达水平、mRNA谱和已知的RAR染色质相关性，研究了激素耗竭和雌激素、他莫昔芬、全反式维甲酸（ATRA）、氟维司群、雌激素受体α（ER）siRNA或维甲酸受体α（RARα）siRNA治疗的影响。竞争性PCR检测乳腺癌细胞系和肿瘤中RARα亚型的表达。在激素耗尽的条件培养基中生长的雌激素敏感的乳腺癌细胞中，不含或含4-羟基三苯氧胺（OH-Tam），基底增殖持续存在。使用siRNA或氟维司群下调ER通过促进细胞周期停滞抑制基础增殖，而不富集ErbB 2/3+过表达细胞。RARα1是乳腺癌细胞系和大多数乳腺肿瘤中表达的唯一RARα亚型，其基础表达受apo-ER支持，但不受OH-Tam影响; RAR-β和-γ不受apo-ER调节。消耗基础RARα1再现了消耗ER的抗增殖作用，而其在ER消耗细胞中的恢复部分地挽救了基础循环。apo-ER和apo-RARα1对他莫昔芬不敏感基因的重叠调控主要包括激活促进细胞周期和有丝分裂的基因和抑制参与生长抑制的基因;这些靶基因通常对ATRA不敏感，但在相关染色质区域富集RAR结合位点。在对ErbB 2/3表达不明显的情况下，ER可通过不受激素耗竭或OH-Tam影响的机制，以及通过维持apo-RARα1的基础表达来调节一组ATRA不敏感基因，从而支持S期细胞的基础分数。由于RARα亚型1在遗传上是冗余的，因此应进一步研究其靶向失活或下调，作为增强激素辅助治疗的潜在手段。
Current hormonal adjuvant therapies for breast cancer including tamoxifen treatment and estrogen depletion are overall tumoristatic and are severely limited by the frequent recurrence of the tumors. Regardless of the resistance mechanism, development and progression of the resistant tumors requires the persistence of a basal level of cycling cells during the treatment for which the underlying causes are unclear. In estrogen-sensitive breast cancer cells the effects of hormone depletion and treatment with estrogen, tamoxifen, all-trans retinoic acid (ATRA), fulvestrant, estrogen receptor α (ER) siRNA or retinoic acid receptor α (RARα) siRNA were studied by examining cell growth and cycling, apoptosis, various mRNA and protein expression levels, mRNA profiles and known chromatin associations of RAR. RARα subtype expression was also examined in breast cancer cell lines and tumors by competitive PCR. Basal proliferation persisted in estrogen-sensitive breast cancer cells grown in hormone depleted conditioned media without or with 4-hydroxytamoxifen (OH-Tam). Downregulating ER using either siRNA or fulvestrant inhibited basal proliferation by promoting cell cycle arrest, without enrichment for ErbB2/3+ overexpressing cells. The basal expression of RARα1, the only RARα isoform that was expressed in breast cancer cell lines and in most breast tumors, was supported by apo-ER but was unaffected by OH-Tam; RAR-β and -γ were not regulated by apo-ER. Depleting basal RARα1 reproduced the antiproliferative effect of depleting ER whereas its restoration in the ER depleted cells partially rescued the basal cycling. The overlapping tamoxifen-insensitive gene regulation by apo-ER and apo-RARα1 comprised activation of mainly genes promoting cell cycle and mitosis and suppression of genes involved in growth inhibition; these target genes were generally insensitive to ATRA but were enriched in RAR binding sites in associated chromatin regions. In hormone-sensitive breast cancer, ER can support a basal fraction of S-phase cells (i) without obvious association with ErbB2/3 expression, (ii) by mechanisms unaffected by hormone depletion or OH-Tam and (iii) through maintenance of the basal expression of apo-RARα1 to regulate a set of ATRA-insensitive genes. Since isoform 1 of RARα is genetically redundant, its targeted inactivation or downregulation should be further investigated as a potential means of enhancing hormonal adjuvant therapy.
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DOI：
10.1073/pnas.0903033106
发表时间：
2009-05-05
影响因子：
11.1
作者：
Cardamone, Maria Dafne;Bardella, Chiara;De Bortoli, Michele
通讯作者：
De Bortoli, Michele
影响因子：
16
作者：
Cvoro, A;Tzagarakis-Foster, C;Leitman, DC
通讯作者：
Leitman, DC
影响因子：
4
作者：
Danforth, DN
通讯作者：
Danforth, DN
影响因子：
45.3
作者：
Dowsett, Mitch;Cuzick, Jack;Peto, Richard
通讯作者：
Peto, Richard
影响因子：
45.3
作者：
Decensi, A;Gandini, S;Lien, EA
通讯作者：
Lien, EA