| Summary: | High mammographic density (MD) increases breast cancer (BC) risk and creates a stiff tissue environment. BC risk is also increased in <i>BRCA1/2</i> gene mutation carriers, which may be in part due to genetic disruption of the tumour suppressor gene Ras association domain family member 1 (<i>RASSF1A</i>), a gene that is also directly regulated by tissue stiffness. High MD combined with <i>BRCA1/2</i> mutations further increase breast cancer risk, yet <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutation status in human mammary tissue obtained after prophylactic mastectomy from women at risk of developing BC. Our results demonstrate that <i>RASSF1A</i> 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 <i>BRCA1,</i> but not <i>BRCA2</i> gene mutated tissues; regional density as measured radiographically repressed RASSF1A in both <i>BRCA1/2</i> mutated tissues. The combinatory effect of high MD and <i>BRCA</i> mutations on breast cancer risk may be due to <i>RASSF1A</i> gene repression in regions of increased tissue stiffness.
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