Abstract
SLPI has been implicated in the progression and metastasis of certain cancers. However, the effects of SLPI seem to be tumor-specific and the mechanisms remain poorly defined. Here, we demonstrate that highly metastatic, triple-negative breast cancer (TNBC) 4T1 cells secreted more SLPI compared to their non-metastatic counterparts. Furthermore, SLPI secretion directly correlated with spontaneous lung metastasis from 4T1 tumors orthotopically implanted in mice. Consistent with our experimental results, we also found that higher SLPI expression levels correlate with worse clinical outcome in basal/TNBC patients. Using high-throughput screening we identified a novel compound, C74, which significantly inhibits SLPI secretion. C74 administration in our mouse model slows the growth of primary 4T1 tumors and inhibits their dissemination to the lung. We also discovered that SLPI physically interacts with the retinoblastoma tumor suppressor protein (Rb) and releases FoxM1 from the Rb-FoxM1 complex, which may activate FoxM1 target genes involved in breast cancer metastasis.
Highlights
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the worst prognosis, despite advancements in modern therapeutics [1]
We discovered that SLPI physically interacts with the retinoblastoma tumor suppressor protein (Rb) and releases FoxM1 from the Rb-FoxM1 complex, which may activate FoxM1 target genes involved in breast cancer metastasis
SLPI secretion is increased in highly metastatic cancer cells and promotes lung metastasis First, to assess if highly metastatic murine breast cancer cells (4T1) secrete different factors from those secreted by strain-matched but non-metastatic cells (67NR), we screened conditioned media from both cell lines using a mouse-specific antibody array
Summary
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the worst prognosis, despite advancements in modern therapeutics [1]. There are some indications that breast cancer cells secrete substances that facilitate dissemination, including osteopontin, hyaluronan, metalloproteases and integrin-binding ligands [3, 4]. It is not clear what role these components play during invasion and metastasis of TNBC, or whether they are valid targets for inhibiting metastasis in patients [5]. Overexpression of SLPI is usually associated with more aggressive, metastatic disease [16,17,18,19]. The details of how SLPI influences tumor aggressiveness, metastatic potential and treatment outcome remain unknown
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