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. 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. 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. 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.

中文翻译：

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未突变的 RRAS2 成为产后相关三阴性乳腺癌的关键癌基因


乳腺癌 (BC) 是女性最常见的癌症，其中三阴性 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，但 TNBC 仍然对当前治疗产生耐药性。尽管生育可降低终生患 BC 的风险，但怀孕会增加产后数年内患 TNBC 的风险。尽管许多基因突变与 BC 相关，但尚无单一基因改变被确定为通用驱动因素。 RRAS2 是一种与 RAS 相关的 GTP 酶，在癌症中很少发现突变。条件性敲入小鼠在乳腺上皮细胞中过表达野生型人 RRAS2。通过 RT-qPCR 分析人类样本队列，以测量 RRAS2 转录表达，并确定 RRAS2 3'UTR 区域中的单核苷酸多态性 (SNP rs8570) 以及肿瘤和非肿瘤中基因组 DNA 扩增的频率人类 BC 样本。在这里，我们表明，野生型 RRAS2 在小鼠中的过度表达足以使 100% 的雌性以妊娠依赖性方式发生 TNBC。在人类 BC 中，野生型 RRAS2 在 68% 的肿瘤中过表达，无论其级别、位置和分子类型如何，超过了任何先前涉及的改变的发生率。尽管如此，RRAS2 过表达在 TNBC 和年轻经产患者中明显更高且更频繁。肿瘤样本中 SNP 位置的替代 C 等位基因的患病率增加，以及 BC 患者肿瘤和血液中频繁的 RRAS2 基因扩增，表明 RRAS2 过度表达与乳腺癌之间存在因果关系。 不带有激活突变的 RRAS2 表达高于正常水平是大多数乳腺癌的关键驱动因素，尤其是三阴性乳腺癌和与妊娠相关的乳腺癌。