Breast cancer was the most frequent and the second most deadly cancer in women in 2018 in China; thus, early diagnosis of breast cancer is important. Studies have reported that tissue stiffness promotes cancer progression through increased collagen or fibrosis. Shear wave elastography (SWE) is a technique for measuring tissue stiffness. However, the mechanisms underlying cancer tissue stiffness or fibrosis are not entirely clear. Hypoxia-inducible factor 1 (HIF-1α) is expressed in response to hypoxia and contributes to tumor progression and metastasis. Kindlin-2 is an important co-activator of integrin. We have reported that Kindlin-2 influences breast cancer stiffness and metastasis. In this study, SWE was used to determine the maximum elasticity (Emax ) of patients before operation or core needle biopsy. The specimens were used for staining. Knockdown, overexpression, co-immunoprecipitation, and immunofluorescence assays were used to explore the relationship between HIF-1α and Kindlin-2. We found that HIF-1α and Kindlin-2 were highly expressed in invasive breast cancer and that the expression levels of HIF-1α and Kindlin-2 were correlated with Emax . HIF-1α interacts with Kindlin-2. Besides, HIF-1α and Kindlin-2 influence the expression of P4HA1, an important protein in collagen biogenesis through the integrin/FAK pathway. Our study first identified a new mechanism of invasive breast cancer stiffness by linking HIF-1α and Kindlin-2 to collagen biogenesis. Therefore, based on SWE, Emax could be a physical biomarker of invasive breast cancer for early, noninvasive diagnosis, and HIF-1α and Kindlin-2 could be pathological markers for early diagnosis and targeted therapy.
Keywords: Breast cancer; Emax; HIF-1α; Kindlin-2; Shear wave elastography.
© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.