YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer.
YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer.
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DOI：
10.3390/cancers13246262
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发表时间：
2021-12-14
期刊：
影响因子：
5.2
通讯作者：
Sossey-Alaoui K
中科院分区：
文献类型：
--
作者：
Rana PS;Wang W;Alkrekshi A;Markovic V;Khiyami A;Chan R;Perzynski A;Joseph N;Sossey-Alaoui K
由于缺乏FDA批准的靶向治疗，三阴性乳腺癌(TNBC)是一种影响许多女性的毁灭性疾病。在缺乏激素和抗体治疗靶向的细胞表面受体ER、PR和Her2的情况下，细胞毒性化疗仍然是主要的治疗过程，由于获得耐药，反应惨淡，并迅速复发。与高加索裔美国人(CA)女性相比，非裔美国人(AA)中TNBC的患病率也高出一倍。这项研究调查了YB1基因在AA和CA妇女TNBC差异中的作用。我们发现与CA相比，YB1在AA起源的TNBC肿瘤中高表达。YB1的表达水平和活性增加与疾病预后差、化疗耐药和肿瘤干细胞(CSC)表型激活有关，AA的表达水平高于CA TNBC肿瘤。更重要的是，我们发现，靶向抑制YB1的表达和活性可以通过增敏化疗和抑制CSCs来显著抑制AA肿瘤的致癌行为。我们的研究首次表明，YB1活性可能是导致TNBC健康差异的主要生物学因素，而针对YB1的专门治疗方法的开发可以减少这些差异。三阴性乳腺癌(TNBC)是乳腺癌(BC)亚型中侵袭性最强的一种。虽然TNBC肿瘤在所有BC亚型中所占比例不到20%，但它们是BC相关死亡的主要原因。更重要的是，当考虑到所有种族/民族的TNBC发病率时，TNBC在所有BC中所占比例不到20%。然而，在非西班牙裔黑人女性中，TNBC的发病率超过40%，这可能是导致该人群BC相关死亡率较高的一个因素。即使在考虑了社会经济地位、医疗保健可获得性和生活方式因素的差异后，这些差距仍然很大。越来越多的证据现在指出，肿瘤固有的生物学机制导致了不同的TNBC疾病负担。在这里，我们证明了YB1，一个多功能基因，在非裔美国人(AA)和高加索美国人(CA)女性之间的TNBC差异中发挥了重要作用。我们发现，在三个独立的TNBC肿瘤队列中，与CA相比，YB1在AA TNBC肿瘤中显著高表达，并且YB1水平的增加与AA合并TNBC患者的生存不良有关。我们在体外和TNBC动物模型中使用了YB1的基因操作和化疗治疗相结合的方法，表明在AA来源的TNBC细胞系中，YB1的致癌活性更强，这是通过增加其致瘤和侵袭行为，通过激活肿瘤干细胞表型和抵抗化疗而实现的。
Triple negative breast cancer (TNBC) is a devastating disease that affects many women, due to the lack of FDA-approved targeted therapy. In the absence of cell surface receptors ER, PR, and Her2 that can be targeted with hormonal and antibody treatments, cytotoxic chemotherapy remains the major course of treatment, with a dismal response and rapid recurrence due to the acquisition of resistance. TNBC is also twice as more prevalent in African American (AA) when compared to Caucasian American (CA) women. This study investigated the role of the YB1 gene in the disparities in TNBC between AA and CA women. We found that YB1 is highly expressed in TNBC tumors of AA origin when compared to CAs. Increased expression levels and activity of YB1 correlates with poor disease outcomes, resistance to chemotherapy, and the activation of the cancer stem cell (CSC) phenotype, with higher levels in AA than in CA TNBC tumors. More importantly, we found that the targeted inhibition of the expression and activity of YB1 significantly inhibited the oncogenic behavior of AA tumors through sensitization to chemotherapy and inhibition of CSCs. Our study is the first to show that YB1 activity may be a major biological contributor to the health disparities in TNBC, and that development of therapies that specifically target YB1 could reduce these disparities. Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.
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DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Anastasiadou E;Jacob LS;Slack FJ
通讯作者：
Slack FJ
影响因子：
2
作者：
Chen X;Li J;Gray WH;Lehmann BD;Bauer JA;Shyr Y;Pietenpol JA
通讯作者：
Pietenpol JA
影响因子：
5.3
作者：
Evdokimova, V;Ruzanov, P;Sorensen, PHB
通讯作者：
Sorensen, PHB
DOI：
10.1006/bbrc.2000.4035
发表时间：
2000-12-29
影响因子：
3.1
作者：
Ceman, S;Nelson, R;Warren, ST
通讯作者：
Warren, ST
DOI：
10.2217/14796694.3.1.55
发表时间：
2007-02-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Finnegan, Timothy J;Carey, Lisa A
通讯作者：
Carey, Lisa A