Faculty of Science, Graduate Program in Molecular Medicine, Mahidol University, Bangkok, Thailand.
Department of Immunology, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand.
Biol Cell. 2024 Apr;116(4):e202300072. doi: 10.1111/boc.202300072. Epub 2024 Mar 21.
The precise etiology of breast cancer is not completely understood, although women with BRCA1 gene mutations have a significantly increased risk of developing the disease. In addition, sporadic breast cancer is frequently associated with decreased BRCA1 gene expression. Growing evidence of Human papillomaviruses (HPVs) infections in breast tumors has raised the possibility of the involvement of HPVs in the pathogenesis of breast cancer. We investigated whether the effects of HPV oncoproteins E6 and E7 were influenced by the expression levels of BRCA1. HPV16E6E7 (prototype or E6D25E/E7N29S Asian variant type) were stably expressed in MDA-MB231 breast cancer cells, wild type for BRCA1, or with BRCA1 knocked down.
Expression of HPV16E6E7 oncogenes did not affect BRCA1 levels and the abundance of HPV16E6E7 was not altered by BRCA1 knockdown. BRCA1 levels did not alter HPV16E6E7-dependent degradation of G1-S cell cycle proteins p53 and pRb. However, we found that the expression of G2-M cell cycle protein cyclin B1 enhanced by HPV16E6E7 was impacted by BRCA1 levels. Especially, we found the correlation between BRCA1 and cyclin B1 expression and this was also confirmed in breast cancer samples from a Thai cohort. We further demonstrated that the combination of HPV oncoproteins and low levels of BRCA1 protein appears to enhance proliferation and invasion. Transactivation activities of HPV16E6E7 on genes regulating cell proliferation and invasion (TGF-β and vimentin) were significantly increased in BRCA1-deficient cells.
Our results indicate that a deficiency of BRCA1 promotes the transactivation activity of HPV16E6E7 leading to increase of cell proliferation and invasion.
HPV infection appears to have the potential to enhance the aggressiveness of breast cancers, especially those deficient in BRCA1.
乳腺癌的确切病因尚未完全阐明，尽管携带 BRCA1 基因突变的女性罹患该疾病的风险显著增加。此外，散发性乳腺癌常与 BRCA1 基因表达降低有关。人乳头瘤病毒（HPV）感染在乳腺癌肿瘤中的大量证据提出了 HPV 可能参与乳腺癌发病机制的可能性。我们研究了 HPV 致癌蛋白 E6 和 E7 的作用是否受 BRCA1 表达水平的影响。HPV16E6E7（原型或 E6D25E/E7N29S 亚洲变异型）在 MDA-MB231 乳腺癌细胞中稳定表达，BRCA1 为野生型或 BRCA1 敲低。
HPV16E6E7 致癌基因的表达并不影响 BRCA1 水平，BRCA1 敲低也不会改变 HPV16E6E7 的丰度。BRCA1 水平不会改变 HPV16E6E7 依赖的 G1-S 细胞周期蛋白 p53 和 pRb 的降解。然而，我们发现 HPV16E6E7 增强的 G2-M 细胞周期蛋白 cyclin B1 的表达受 BRCA1 水平的影响。特别是，我们发现 BRCA1 和 cyclin B1 表达之间存在相关性，这在泰国队列的乳腺癌样本中也得到了证实。我们进一步证明，HPV 致癌蛋白与低水平的 BRCA1 蛋白的组合似乎增强了增殖和侵袭。BRCA1 缺陷细胞中 HPV16E6E7 对调节细胞增殖和侵袭的基因（TGF-β 和波形蛋白）的转录激活活性显著增加。
我们的结果表明，BRCA1 缺陷促进了 HPV16E6E7 的转录激活活性，导致细胞增殖和侵袭增加。
HPV 感染似乎有可能增强乳腺癌的侵袭性，特别是那些 BRCA1 缺乏的乳腺癌。
