Abstract
It is well documented that the tumor microenvironment profoundly impacts the etiology and progression of breast cancer, yet the contribution of the resident microbiome within breast tissue remains poorly understood. Tumor microenvironmental conditions, such as hypoxia and dense tumor stroma, predispose progressive phenotypes and therapy resistance, however the role of bacteria in this interplay remains uncharacterized. We hypothesized that the effect of individual bacterial secreted molecules on breast cancer viability and proliferation would be modulated by these tumor-relevant stressors differentially for cells at varying stages of progression. To test this, we incubated human breast adenocarcinoma cells (MDA-MB-231, MCF-DCIS.com) and non-malignant breast epithelial cells (MCF-10A) with N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a quorum-sensing molecule from Pseudomonas aeruginosa that regulates bacterial stress responses. This molecule was selected because Pseudomonas was recently characterized as a significant fraction of the breast tissue microbiome and OdDHL is documented to impact mammalian cell viability. After OdDHL treatment, we demonstrated the greatest decrease in viability with the more malignant MDA-MB-231 cells and an intermediate MCF-DCIS.com (ductal carcinoma in situ) response. The responses were also culture condition (i.e. microenvironment) dependent. These results contrast the MCF-10A response, which demonstrated no change in viability in any culture condition. We further determined that the observed trends in breast cancer viability were due to modulation of proliferation for both cell types, as well as the induction of necrosis for MDA-MB-231 cells in all conditions. Our results provide evidence that bacterial quorum-sensing molecules interact with the host tissue environment to modulate breast cancer viability and proliferation, and that the effect of OdDHL is dependent on both cell type as well as microenvironment. Understanding the interactions between bacterial signaling molecules and the host tissue environment will allow for future studies that determine the contribution of bacteria to the onset, progression, and therapy response of breast cancer.
Highlights
The tumor microenvironment is a widely recognized and well-studied contributor to cancer dynamics, for breast cancer
We found that the response to OdDHL was dependent on cell-type, and the culture condition
In the 2D/hypoxia condition, that relative viability was increased to 60.6% (± 2.2%) and in 30]. Threedimensional (3D)/normoxia condition, that viability was increased to 81.9% (± 2.2%) (Fig 1C and 1D, respectively)
Summary
The tumor microenvironment is a widely recognized and well-studied contributor to cancer dynamics, for breast cancer. Even fewer have investigated how small molecules released from resident bacteria may interact with cells in the presence of other critical microenvironmental factors, e.g. tumor hypoxia, to regulate cancer progression. In an effort to address these questions, we investigated interactions between the quorum-sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) and the breast tumor relevant microenvironmental cues of a stiff collagen-derived tissue mimic and hypoxia. This representative study will aid in our understanding of how the understudied breast tissue microbiome may contribute to disease phenotypes, patient-topatient variability, and cancer progression
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