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Androgen receptor and FOXA1 coexpression define a "luminal-AR" subtype of feline mammary carcinomas, spontaneous models of breast cancer.
BMC Cancer ( IF 3.4 ) Pub Date : 2019-12-30 , DOI: 10.1186/s12885-019-6483-6
Elie Dagher 1 , Violette Royer 1 , Paul Buchet 1 , Jérôme Abadie 1, 2 , Delphine Loussouarn 2, 3 , Mario Campone 2, 4 , Frédérique Nguyen 1, 2, 4
Affiliation  

BACKGROUND Invasive mammary carcinomas that spontaneously develop in female cats are associated with high mortality, and resemble the most aggressive human breast cancers, especially triple-negative breast cancer (TNBC). Transcriptome studies showed that TNBCs are a heterogeneous group that includes a potentially hormone-dependent subtype named luminal-AR. Some authors proposed an immunohistochemical definition of the luminal-AR subtype, which is not only positive for Androgen Receptor (AR), but also either positive for the transcription factor Forkhead box A1 (FOXA1), or negative for basal markers. The objectives of this study were to describe AR and FOXA1 expressions in feline mammary carcinomas (FMCs), their prognostic value, and if their coexpression could define a "luminal-AR" subtype of triple-negative mammary carcinomas in cats. METHODS In a previously described retrospective cohort of 180 female cats with FMCs, with a 2-year follow-up post-mastectomy, we assessed AR, FOXA1, ER, PR, Ki-67, HER2, and CK14 expressions by automated immunohistochemistry. RESULTS Of the 180 FMCs, 57 (32%) were luminal; i.e., ER and/or PR positive, and 123 (68%) were triple-negative (ER-, PR- and HER2-) FMCs. AR overexpression (found in 33 cases/180, 18%) and FOXA1 index ≥1% (64/180, 36%) were associated with a longer disease-free interval, overall survival, and cancer-specific survival in cats with FMC. Analysis of AR, FOXA1 and CK14 coexpression in triple-negative FMCs showed that AR+ triple-negative FMCs were heterogeneous: there existed an AR+ FOXA1+ CK14- subgroup (n = 7) associated with a better cancer-specific survival by multivariate survival analysis (HR = 0.26, 95% CI: 0.07-0.89, p = 0.03) compared to AR+ FOXA1-CK14+ triple-negative FMCs (n = 46) (HR = 1.00), independently of the pathologic tumor size and pathologic nodal stage. The non-basal-like subtype of triple-negative FMCs that coexpresses AR and FOXA1 (the AR+ FOXA1+ CK14- subgroup) could represent the equivalent of the luminal-AR subgroup of human triple-negative breast cancer. CONCLUSIONS We identified an AR+ FOXA1+ CK14- subgroup of triple-negative FMCs that might correspond to the luminal-AR subgroup of human triple-negative breast cancers. Cats with FMC may be interesting spontaneous animal models to investigate new strategies targeting the androgen receptor, especially in the aggressive subtype of AR+ basal-like triple-negative mammary carcinomas with loss of FOXA1 expression (the AR+ FOXA1-CK14+ subgroup).

中文翻译:

雄激素受体和FOXA1共表达定义了猫乳腺癌的“ luminal-AR”亚型,这是乳腺癌的自发模型。

背景技术在雌性猫中自发发展的浸润性乳腺癌与高死亡率相关,并且类似于最具侵略性的人乳腺癌,特别是三阴性乳腺癌(TNBC)。转录组研究表明,TNBC是一个异质性基团,其中包括一种可能的激素依赖性亚型,称为腔内AR。一些作者提出了管腔AR亚型的免疫组织化学定义,该定义不仅对雄激素受体(AR)呈阳性,而且对转录因子叉头盒A1(FOXA1)呈阳性,或者对基础标志物呈阴性。这项研究的目的是描述猫乳腺癌(FMC)中AR和FOXA1的表达,其预后价值以及它们的共表达是否可以定义猫中三阴性乳腺癌的“管腔AR”亚型。方法在先前描述的180例FMC雌性猫的回顾性队列研究中,进行了2年的乳房切除术后随访,我们通过自动免疫组织化学评估了AR,FOXA1,ER,PR,Ki-67,HER2和CK14的表达。结果在180个FMC中,有57个(32%)为管腔。即ER和/或PR阳性,而123(68%)是三阴性(ER-,PR-和HER2-)FMC。AR过度表达(33例/ 180,占18%)和FOXA1指数≥1%(64 / 180,36%)与FMC猫的无病间隔时间更长,总体生存率和癌症特异性生存率相关。对三阴性FMC中AR,FOXA1和CK14共表达的分析表明,AR +三阴性FMC是异质性的:通过多因素生存分析(HR),存在一个AR + FOXA1 + CK14-亚组(n = 7),具有更好的癌症特异性生存率= 0.26,95%CI:0.07-0.89,与AR + FOXA1-CK14 +三阴性FMC(n = 46)(HR = 1.00)相比,p = 0.03),而与病理肿瘤大小和病理结节分期无关。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。03)与AR + FOXA1-CK14 +三阴性FMC(n = 46)(HR = 1.00)进行比较,与病理肿瘤大小和病理结节分期无关。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。03)与AR + FOXA1-CK14 +三阴性FMC(n = 46)(HR = 1.00)进行比较,与病理肿瘤大小和病理结节分期无关。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。与病理性肿瘤大小和病理性淋巴结分期无关。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。与病理性肿瘤大小和病理性淋巴结分期无关。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。共表达AR和FOXA1的三阴性FMC的非基底样亚型(AR + FOXA1 + CK14-亚型)可以代表人类三阴性乳腺癌的腔-AR亚型。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。结论我们确定了三阴性FMC的AR + FOXA1 + CK14-亚组,可能与人类三阴性乳腺癌的管腔-AR亚组相对应。患有FMC的猫可能是有趣的自发动物模型,以研究针对雄激素受体的新策略,尤其是在具有FOXA1表达缺失的AR +基底样三阴性乳腺癌的侵略性亚型中(AR + FOXA1-CK14 +亚组)。
更新日期:2019-12-31
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