Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells

Abstract

Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. Neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 were specifically overexpressed in 231-BR cells. Pathway-analyses revealed activation of signaling networks that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all except BMD-231 cells. We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR). Dimethylaminoparthenolide inhibited NF-κB activity, LYPD1 expression, and proliferation of 231-BR and 4T1-BR cells. Thus, transcriptome change enabling adaptation to host organs is likely one of the mechanisms associated with organ-specific metastasis and could potentially be targeted therapeutically.

A system for detecting high impact-low frequency mutations in primary tumors and metastases

“…Here we document feasibility of both aspects. Third, this study supports our previous publication demonstrating organ-site specific adaptive signaling pathway activation in metastatic cells 6 . Despite differences in the cancer type of origin, liver metastases showed few consistent mutation patterns and/or pathway aberrations, suggesting that organ site of metastasis influences mutation spectrum in metastases.…”

“…Our previous work in animal models demonstrated brain metastatic cells undergo unique gene expression changes that allow them to adapt to brain microenvironment 6 . However, to our knowledge, attempts to cultivate human brain metastatic tumors cells in vitro and identify mutations have been limited.…”

Endocan as a prognostic biomarker of triple-negative breast cancer

“…In fact, mouse endocan is less glycanated than human endocan, and its biological properties are completely opposite to human endocan [26, 27]. Unlike MDA-MB-231SCP2, some other metastatic human TNBC cell lines were reported to overexpress ESM1 [28]; however, no proliferation rates were available for those cell lines. These observations may indicate that overexpression of human ESM1 leads to rapid proliferation and might result in distant metastases for human TNBC cells, but also imply that metastatic human TNBC cells might not necessarily overexpress human ESM1 .…”

Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain

“…While the exact mechanism of brain metastasis remains unclear, accumulated studies have proved that the brain metastatic process is a complex process involving multiple steps [25]. First, tumor cells escape from the primary tumor site by losing cell-cell adhesion and gaining motility, enabling them to invade the surrounding tissues [26].…”