Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, The Research Building, Room E410, Washington, DC, 20057, USA.
The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University Research Center, Arlington, VA, USA.
Breast Cancer Res. 2018 Aug 30;20(1):99. doi: 10.1186/s13058-018-1034-7.
While many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters.
Male mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses.
We found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent.
Our study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.
虽然许多研究表明，妊娠期间的母体因素会影响后代的癌症风险，但很少有研究调查父体暴露对后代罹患这种疾病风险的影响。人群研究通常显示，出生体重与乳腺癌风险之间呈 U 形关联，与平均出生体重相比，高出生体重和低出生体重都会增加风险。在这里，我们研究了父体营养不良是否会调节女儿的出生体重和随后的乳腺癌风险。
雄性小鼠从 3 至 10 周龄时，以含 17.7%（对照）或 8.9%（低蛋白（LP））能量的基于 AIN93G 的饮食喂养，蛋白质中的能量来自蛋白质。无论哪一组的雄性都与以对照饮食喂养的雌性交配。来自对照和 LP 父亲的雌性后代接受 7,12-二甲基苯并[a]蒽（DMBA）处理以启动乳腺致癌作用。来自父亲的成熟精子和来自雌性后代的乳腺组织和肿瘤用于表观遗传和其他分子分析。
我们发现，父体营养不良会降低女儿的出生体重，并导致其乳腺组织和肿瘤发生表观遗传和代谢重编程。LP 父亲的女儿乳腺癌发生率更高，肿瘤的发生更早，生长速度更快。能量传感器，即 AMP 激活的蛋白激酶（AMPK）途径，在 LP 女儿的乳腺组织和肿瘤中均受到抑制，随后哺乳动物雷帕霉素靶蛋白（mTOR）信号被激活。此外，LP 乳腺肿瘤表现出改变的氨基酸代谢，利用更多的谷氨酰胺。这些变化与调节乳腺组织和肿瘤中这些途径的非编码 RNA 的改变有关。重要的是，我们在来自低出生体重普遍存在的人群的女性乳腺癌肿瘤中检测到我们动物模型中存在的一些相同的 microRNA/靶基因的改变。
我们的研究表明，祖先的父体营养不良通过可能为癌细胞提供代谢优势，在编程后代的癌症风险和表型方面发挥作用。
