PDF(Pubmed)
Abstract：
BACKGROUND: Breast cancer (BC) is the most common cancer in women, with triple negative BC (TNBC) accounting for 20% of cases. While early detection and targeted therapies have improved overall life expectancy, TNBC remains resistant to current treatments. Although parity reduces the lifetime risk of developing BC, pregnancy increases the risk of developing TNBC for years after childbirth. Although numerous gene mutations have been associated with BC, no single gene alteration has been identified as a universal driver. RRAS2 is a RAS-related GTPase rarely found mutated in cancer.
METHODS: Conditional knock-in mice were generated to overexpress wild type human RRAS2 in mammary epithelial cells. A human sample cohort was analyzed by RT-qPCR to measure RRAS2 transcriptional expression and to determine the frequency of both a single-nucleotide polymorphism (SNP rs8570) in the 3\'UTR region of RRAS2 and of genomic DNA amplification in tumoral and non-tumoral human BC samples.
RESULTS: Here we show that overexpression of wild-type RRAS2 in mice is sufficient to develop TNBC in 100% of females in a pregnancy-dependent manner. In human BC, wild-type RRAS2 is overexpressed in 68% of tumors across grade, location, and molecular type, surpassing the prevalence of any previously implicated alteration. Still, RRAS2 overexpression is notably higher and more frequent in TNBC and young parous patients. The increased prevalence of the alternate C allele at the SNP position in tumor samples, along with frequent RRAS2 gene amplification in both tumors and blood of BC patients, suggests a cause-and-effect relationship between RRAS2 overexpression and breast cancer.
CONCLUSIONS: Higher than normal expression of RRAS2 not bearing activating mutations is a key driver in the majority of breast cancers, especially those of the triple-negative type and those linked to pregnancy.
METHODS: Conditional knock-in mice were generated to overexpress wild type human RRAS2 in mammary epithelial cells. A human sample cohort was analyzed by RT-qPCR to measure RRAS2 transcriptional expression and to determine the frequency of both a single-nucleotide polymorphism (SNP rs8570) in the 3\'UTR region of RRAS2 and of genomic DNA amplification in tumoral and non-tumoral human BC samples.
RESULTS: Here we show that overexpression of wild-type RRAS2 in mice is sufficient to develop TNBC in 100% of females in a pregnancy-dependent manner. In human BC, wild-type RRAS2 is overexpressed in 68% of tumors across grade, location, and molecular type, surpassing the prevalence of any previously implicated alteration. Still, RRAS2 overexpression is notably higher and more frequent in TNBC and young parous patients. The increased prevalence of the alternate C allele at the SNP position in tumor samples, along with frequent RRAS2 gene amplification in both tumors and blood of BC patients, suggests a cause-and-effect relationship between RRAS2 overexpression and breast cancer.
CONCLUSIONS: Higher than normal expression of RRAS2 not bearing activating mutations is a key driver in the majority of breast cancers, especially those of the triple-negative type and those linked to pregnancy.
摘要：
背景：乳腺癌（BC）是女性最常见的癌症，三阴性BC（TNBC）占病例的20％。虽然早期检测和靶向治疗提高了总体预期寿命，TNBC仍然对目前的治疗具有抗性。尽管平价降低了发展BC的终生风险，怀孕会增加分娩后数年发生TNBC的风险。尽管许多基因突变与BC有关，没有单一的基因改变被认为是一个普遍的驱动因素。RRAS2是在癌症中很少发现突变的RAS相关GTP酶。
方法:产生条件敲入小鼠以在乳腺上皮细胞中过表达野生型人RRAS2。通过RT-qPCR分析人类样品组以测量RRAS2转录表达并确定RRAS2的3'UTR区域中的单核苷酸多态性（SNPrs8570）的频率以及肿瘤和非肿瘤人类BC样品中的基因组DNA扩增的频率。
结果：在这里，我们表明小鼠中野生型RRAS2的过表达足以以妊娠依赖性方式在100％的雌性中发展TNBC。在人类BC，野生型RRAS2在68%的肿瘤中过度表达，location,和分子类型，超过了以前任何牵连的改变的普遍性。尽管如此，RRAS2过表达在TNBC和年轻患者中明显更高，更频繁。在肿瘤样本中SNP位置的替代C等位基因的患病率增加，伴随着在BC患者的肿瘤和血液中频繁的RRAS2基因扩增，提示RRAS2过表达与乳腺癌之间存在因果关系。
结论：在大多数乳腺癌中，不携带激活突变的RRAS2高于正常表达是一个关键驱动因素，尤其是那些三阴性和那些与怀孕有关的。
方法:产生条件敲入小鼠以在乳腺上皮细胞中过表达野生型人RRAS2。通过RT-qPCR分析人类样品组以测量RRAS2转录表达并确定RRAS2的3'UTR区域中的单核苷酸多态性（SNPrs8570）的频率以及肿瘤和非肿瘤人类BC样品中的基因组DNA扩增的频率。
结果：在这里，我们表明小鼠中野生型RRAS2的过表达足以以妊娠依赖性方式在100％的雌性中发展TNBC。在人类BC，野生型RRAS2在68%的肿瘤中过度表达，location,和分子类型，超过了以前任何牵连的改变的普遍性。尽管如此，RRAS2过表达在TNBC和年轻患者中明显更高，更频繁。在肿瘤样本中SNP位置的替代C等位基因的患病率增加，伴随着在BC患者的肿瘤和血液中频繁的RRAS2基因扩增，提示RRAS2过表达与乳腺癌之间存在因果关系。
结论：在大多数乳腺癌中，不携带激活突变的RRAS2高于正常表达是一个关键驱动因素，尤其是那些三阴性和那些与怀孕有关的。
