Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses.
Age alters the oncogenic trajectory toward luminal mammary tumors that activate unfolded proteins responses.
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DOI：
10.1111/acel.13665
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发表时间：
2022-10
期刊：
影响因子：
7.8
通讯作者：
Germain, Doris
中科院分区：
文献类型：
--
作者：
Jenkins, Edmund Charles;Chattopadhyay, Mrittika;Gomez, Maria;Torre, Denis;Ma'ayan, Avi;Torres-Martin, Miguel;Sia, Daniela;Germain, Doris
关键词：
在乳腺癌研究中使用小鼠模型的一个主要限制是大多数小鼠发生雌激素受体α（ERα）阴性乳腺肿瘤，而在人类中，大多数乳腺癌是ERα阳性的。因此，开发最能模拟人类疾病的小鼠模型是根本需要。在这里，使用诱导型MMTV‐rtTA/TetO‐NeuNT小鼠模型，我们表明，尽管由相同的癌基因驱动，但年轻小鼠的乳腺肿瘤是ERα阴性的，而老年小鼠的乳腺肿瘤是ERα阳性的。为了进一步阐明这一观察结果的机制，我们进行了RNAseq分析，并鉴定了在老年女性来源的乳腺肿瘤中独特表达的基因。我们发现这些基因参与线粒体UPR的ERα轴的激活和ERα介导的XBP-1 s的调节，XBP-1 s是一种参与内质网UPR的基因。总的来说，我们的研究结果表明，衰老改变了乳腺癌ERα阳性亚型的致癌轨迹，老年小鼠乳腺肿瘤的特征是ERα调节的多种UPR应激反应的上调。老年女性倾向于发展雌激素受体α（ERα）阳性乳腺癌，尽管雌激素水平较低，但这一基本观察结果从未在小鼠中重现，其中大多数研究都是在年轻小鼠中进行的。我们发现，相同的癌基因在年轻和老年小鼠乳腺中的表达分别导致ER α阴性和ERα阳性。󠆴老年小鼠肿瘤的特征在于由ER α驱动的多个未折叠蛋白反应（UPR）的激活，这在年轻小鼠的ER α阳性细胞中未发现。󠆴󠆴这些发现表明，年龄不仅决定了乳腺癌亚型，还决定了ER α转录程序。󠆴
A major limitation in the use of mouse models in breast cancer research is that most mice develop estrogen receptor‐alpha (ERα)‐negative mammary tumors, while in humans, the majority of breast cancers are ERα‐positive. Therefore, developing mouse models that best mimic the disease in humans is of fundamental need. Here, using an inducible MMTV‐rtTA/TetO‐NeuNT mouse model, we show that despite being driven by the same oncogene, mammary tumors in young mice are ERα‐negative, while they are ERα‐positive in aged mice. To further elucidate the mechanisms for this observation, we performed RNAseq analysis and identified genes that are uniquely expressed in aged female‐derived mammary tumors. We found these genes to be involved in the activation of the ERα axis of the mitochondrial UPR and the ERα‐mediated regulation of XBP‐1s, a gene involved in the endoplasmic reticulum UPR. Collectively, our results indicate that aging alters the oncogenic trajectory towards the ERα‐positive subtype of breast cancers, and that mammary tumors in aged mice are characterized by the upregulation of multiple UPR stress responses regulated by the ERα. Older women tend to develop estrogen receptor‐alpha (ER󠆴α)‐positive breast cancers, despite having lower levels of estrogen, but this fundamental observation has never been recapitulated in mice, where most studies are performed in young mice. We show that the expression of the same oncogene in the mammary glands of young and aged mice leads to ER󠆴α‐negative and ER󠆴α‐positive, respectively. Tumors in aged mice are characterized by the activation of multiple unfolded protein responses (UPR) driven by the ER󠆴α that is not found in ER󠆴α‐positive cells from young mice. These findings suggest that age dictates not only breast cancer subtypes but also ER󠆴α transcriptional programs.
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影响因子：
4.6
作者：
Jenkins EC;O'Connell MJ;Manfredi G;Germain D
通讯作者：
Germain D
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
3.2
作者：
Gravekamp, C;Sypniewska, R;Reddick, R
通讯作者：
Reddick, R
影响因子：
11.4
作者：
Klinge, Carolyn M.
通讯作者：
Klinge, Carolyn M.
影响因子：
3.5
作者：
Rezakhaniha, R.;Agianniotis, A.;Stergiopulos, N.
通讯作者：
Stergiopulos, N.