Abstract
Inflammation is associated with the development of several cancers, including breast cancer. However, the molecular mechanisms driving breast cancer initiation or enhancement by inflammation are yet to be deciphered. Hence, we opted to investigate the role of inflammation in initiating and enhancing tumor-like phenotypes in nontumorigenic, pretumorigenic, and tumorigenic breast epithelial cells. Noncytotoxic endotoxin (ET) concentrations capable of inducing an inflammatory phenotype were determined for the different cell lines. Results showed that short-term ET exposure upregulated matrix metalloproteinase-9 (MMP-9) activity in nontumorigenic mammary epithelial cells of mouse (SCp2) and human origins (HMT-3522 S1; S1) and upregulated inflammatory mediators including nitric oxide (NO) and interleukin 1-β in tumorigenic human breast cells (MDA-MB-231), all in a dose-dependent manner. Long-term ET treatment, but not short-term, triggered the migration of SCp2 cells, and proliferation and migration of tumorigenic human breast cells MCF-7 and MDA-MB-231. Both short- and long-term ET exposures preferentially enhanced the invasion of pretumorigenic S1-connexin 43 knockout (Cx43-KO S1) cells compared to their nontumorigenic S1 counterparts. Moreover, both ET exposures disrupted lumen formation and apicolateral distribution of β-catenin in 3D cultures of S1 cells. In conclusion, ET treatment at concentrations that elicited inflammatory phenotype triggered tumor initiation events in nontumorigenic and pretumorigenic breast cells, and increased tumorigenicity of breast cancer cells. Our findings highlight the role of inflammation in enhancing migration, invasion, and loss of normal 3D morphology and suggest that such inflammatory insults can “add injury” to pretumorigenic and tumorigenic breast epithelial cells.
Highlights
Inflammation is implicated in the initiation processes of several cancers [1]
ET was used at 0.1 μg/ml for the treatment of normal mouse mammary epithelial SCp2 cells, at 10 μg/ml for nontumorigenic human mammary epithelial S1 cells and their pretumorigenic counterparts, connexin 43 (Cx43)-KO S1 cells [21], and at 1 μg/ml for the tumorigenic cell lines including human breast cancer cells of intermediate (MCF-7) and high invasiveness (MDA-MB-231)
Our study investigates the role of ET-induced inflammatory insult in breast cancer initiation events using nontumorigenic (SCp2 and S1) rodent mammary and human breast epithelial cells, respectively, and whether such an insult can “add injury” to pretumorigenic (Cx43-KO S1) or tumorigenic breast cells (MCF-7 and MDA-MB-231)
Summary
Inflammation is implicated in the initiation processes of several cancers [1]. chronic inflammation has long been associated with cancer development [2]. C-reactive protein, an inflammatory marker, were associated with an increase in the risk of breast cancer [14]. Us, studying the inflammatory biomarkers, cellular mediators, and their downstream effects due to a chronic insult is important for understanding cancer initiation [16]. In light of the above, little is known about the effect of ET-induced chronic inflammation on breast cancer initiation events and whether such inflammation would trigger loss of 3D morphological differentiation and apical polarity that characterize normal breast tissue. We propose that ET-induced inflammation enhances the tumor initiation events in nontumorigenic and pretumorigenic mammary epithelial cells and increases tumorigenicity of breast cancer cell lines, suggesting that inflammatory insults trigger tumor initiation events but can “add injury” to pretumorigenic and tumorigenic breast cells
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