Are the estrogen receptor and SIRT3 axes of the mitochondrial UPR key regulators of breast cancer sub-type determination according to age?
Are the estrogen receptor and SIRT3 axes of the mitochondrial UPR key regulators of breast cancer sub-type determination according to age?
复制标题
线粒体UPR的雌激素受体和SIRT3轴是根据年龄确定乳腺癌亚型的关键调节因子吗？
DOI：
10.1002/aac2.12035
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
Germain D
中科院分区：
文献类型：
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作者：
Jenkins EC;Chattopadhyay M;Germain D
衰老是患乳腺癌的主要危险因素。尽管绝经后妇女雌激素水平较低，但老年妇女雌激素受体α（ERα）阳性乳腺癌的发病率较高。相反，雌激素水平升高的年轻女性往往会患上ERα阴性疾病，这与更高的转移率相关。这一观点提出了一个统一的模型，围绕线粒体生物学在癌症和衰老中的重要性来解释这些观察结果。线粒体对于癌细胞的存活是必不可少的，因此维持癌细胞中线粒体网络功能的途径在癌细胞的存活中发挥关键作用。ERα和线粒体sirtuin-3（SIRT 3）是线粒体未折叠蛋白反应（UPRmt）的关键参与者。UPRmt是一种复杂的逆行信号级联反应，调节线粒体和细胞核之间的通讯，以恢复线粒体适应性，以响应氧化应激。SIRT 3是衰老的主要调节因子。它的水平随着年龄的增长而下降，在百岁老人中观察到单核苷酸多态性（SNP）保持其较高水平的表达。我们提出了一个模型，UPRmt的ERα轴的作用，以弥补随着年龄的增长观察到的SIRT 3的损失，并成为UPRmt的主导轴，以保持线粒体的完整性，在转化过程中，从而解释了ERα阳性管腔细胞的选择性优势，在乳腺癌中产生的老年妇女。衰老是患乳腺癌的主要危险因素。尽管绝经后妇女雌激素水平较低，但老年妇女雌激素受体α（ERα）阳性乳腺癌的发病率较高。相反，雌激素水平升高的年轻女性倾向于发展与较高转移率相关的ERα阴性疾病。这一观点提出了一个统一的模型，围绕SIRT 3和雌激素受体轴之间的开关线粒体未折叠的蛋白质响应与年龄来解释这些观察结果。
Aging is a major risk factor of developing breast cancer. Despite the fact that post-menopausal women have lower levels of estrogen, older women have a higher rate of estrogen receptor alpha (ERα) positive breast cancer. Conversely, young women who have elevated levels of estrogen tend to develop ERα negative disease that is associated with higher rate of metastasis. This perspective proposes a unifying model centered around the importance of mitochondrial biology in cancer and aging to explain these observations. Mitochondria are essential for the survival of cancer cells and therefore pathways that maintain the functionality of the mitochondrial network in cancer cells fulfill a critical role in the survival of cancer cells. The ERα and the mitochondrial sirtuin-3 (SIRT3) have been reported to be key players of the mitochondrial unfolded protein response (UPRmt) . The UPRmt is a complex retrograde signaling cascade that regulates the communication between the mitochondria and the nucleus to restore mitochondrial fitness in response to oxidative stress . SIRT3 is a major regulator of aging . Its level decreases with age and single nucleotide polymorphisms (SNPs) that preserve its expression at higher levels are observed in centenarians . We propose a model whereby the ERα axis of the UPRmt acts to compensate for the loss of SIRT3 observed with age, and becomes the dominant axis of the UPRmt to maintain the integrity of the mitochondria during transformation, thus explaining the selective advantage of ERα positive luminal cells in breast cancer arising from older women. Aging is a major risk factor of developing breast cancer. Despite the fact that post-menopausal women have lower levels of estrogen, older women have a higher rate of estrogen receptor alpha (ERα) positive breast cancer. Conversely, young women who have elevated levels of estrogen tend to develop ERα negative disease that is associated with higher rate of metastasis. This perspective proposes a unifying model centered around the switch between the SIRT3 and estrogen receptor axes of the mitochondrial unfolded protein response with age to explain these observations.