Date of Award
Doctor of Philosophy
Jay Whelan, Guoxen Chen, Hwa-Chain Wang
Breast cancer, surpassing lung cancer with the highest estimated new cases, is closely associated with obesity. Cancer research continues to divulge the complexity of the disease including the recognition that stromal cells must cooperate with the cancerous epithelium for cancer growth and metastasis.
Parabens are a class of esters of 4-hydroxybenzoic acid that is ubiquitous in the environment, and act as anti-microbial agents that sustain the shelf-life of personal care products, pharmaceuticals, food, etc. Parabens are classified as endocrine disrupting chemicals, are estrogenic, and bioaccumulate within adipose tissue.
Activation of fibroblasts is caused by tissue damage leading to the release of inflammatory cytokines to stimulate wound healing. Low dose (0.02, 0.1, and 1 μM) methyl-, propyl, and butylparaben (MP, PP, and BP) treatment onto murine 3T3-L1 and human primary breast (BRF) fibroblasts led to an inflammatory response by the upregulation of inflammatory cytokines including interleukin-1β (IL-1β) and cyclooxygenase-2 (COX2) via activation of the NF-κB pathway (Chapter III). MP, PP, and BP also upregulated matrix metalloproteinase-9 (MMP9), indicating potential influence in metastasis. Paraben-treated fibroblasts also increased the mRNA expression of CYP19A1 otherwise known as aromatase, which influences the conversion of androgen to estradiol. Secretions from paraben-treated fibroblasts also obtained the ability to enhance proliferation of estrogen receptor positive (ER+) breast cancer cells (MCF7).
To evaluate the contribution of adipocytes, 3T3-L1 and BRF adipocytes were treated with MP, PP, and BP and induced upregulation IL-1β, COX2, MMP9, and CYP19A1 (Chapter IV). The secretions from paraben-treated adipocytes also enhanced the proliferation of MCF7 cells.
In conclusion, we have shown that environmental achievable low doses of parabens enhance the inflammatory response of stromal fibroblasts and adipocytes, and the secretions produced from paraben exposure enhance the proliferation of breast cancer cells. Our results support the existing evidence that paraben exposure may lead to increased risks of breast cancer and suggest the stromal link between parabens and breast cancer. Further v studies are warranted to confirm the effects of parabens on breast stromal cells and carcinogenesis in vivo and to establish the role of NF-kB pathway.
Hager, Emily, "Paraben and Breast Cancer: A Stromal Link. " PhD diss., University of Tennessee, 2020.