Reye Gina, Huang Xuan, Britt Kara L, Meinert Christoph, Blick Tony, Xu Yannan, Momot Konstantin I, Lloyd Thomas, Northey Jason J, Thompson Erik W, Hugo Honor J
School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4006, Australia.
Translational Research Institute, Woolloongabba, QLD 4102, Australia.
Cancers (Basel). 2021 Jun 29;13(13):3251. doi: 10.3390/cancers13133251.
High mammographic density (MD) increases breast cancer (BC) risk and creates a stiff tissue environment. BC risk is also increased in gene mutation carriers, which may be in part due to genetic disruption of the tumour suppressor gene Ras association domain family member 1 (), a gene that is also directly regulated by tissue stiffness. High MD combined with mutations further increase breast cancer risk, yet mutations alone or in combination do not increase MD. The molecular basis for this additive effect therefore remains unclear. We studied the interplay between MD, stiffness, and mutation status in human mammary tissue obtained after prophylactic mastectomy from women at risk of developing BC. Our results demonstrate that expression increased in MCF10DCIS.com cell cultures with matrix stiffness up until ranges corresponding with BiRADs 4 stiffnesses (~16 kPa), but decreased in higher stiffnesses approaching malignancy levels (>50 kPa). Similarly, higher RASSF1A protein was seen in these cells when co-cultivated with high MD tissue in murine biochambers. Conversely, local stiffness, as measured by collagen I versus III abundance, repressed RASSF1A protein expression in but not gene mutated tissues; regional density as measured radiographically repressed RASSF1A in both mutated tissues. The combinatory effect of high MD and mutations on breast cancer risk may be due to gene repression in regions of increased tissue stiffness.
乳腺钼靶高密度（MD）会增加患乳腺癌（BC）的风险，并形成僵硬的组织环境。基因突变携带者患BC的风险也会增加，这可能部分归因于肿瘤抑制基因Ras关联结构域家族成员1（RASSF1A）的基因破坏，该基因也受组织硬度直接调控。高MD与RASSF1A突变共同作用会进一步增加患乳腺癌的风险，然而单独的RASSF1A突变或其与高MD共同作用都不会增加MD。因此，这种累加效应的分子基础仍不清楚。我们研究了MD、硬度和RASSF1A突变状态在有患BC风险的女性预防性乳房切除术后获得的人乳腺组织中的相互作用。我们的结果表明，在MCF10DCIS.com细胞培养物中，随着基质硬度增加直至达到与乳腺影像报告和数据系统（BiRADs）4级硬度（约16千帕）相对应的范围，RASSF1A表达增加，但在接近恶性水平（>50千帕）的更高硬度下表达降低。同样，当这些细胞在小鼠生物腔室中与高MD组织共培养时，可见较高的RASSF1A蛋白。相反，通过I型与III型胶原蛋白丰度测量的局部硬度在RASSF1A基因未突变的组织中抑制RASSF1A蛋白表达；通过影像学测量的区域密度在RASSF1A基因突变的两种组织中均抑制RASSF1A表达。高MD与RASSF1A突变对乳腺癌风险的联合作用可能是由于在组织硬度增加区域的RASSF1A基因受到抑制。
