Electronic Thesis/Dissertation
The involvement of non-genomic signaling in inflammatory breast cancer Open Access
Although Inflammatory Breast Cancer (IBC) is a rare and an aggressive type of locally advanced breast cancer with one of the worst prognosis, little work has been done in identifying the molecular signature of the disease. The present study was performed to identify these signatures with respect to hormonal dependence of IBC. We have identified the presence of ERα variants, ERα36 and ERα46 in IBC cell lines SUM149 and SUM190.The variants as well as a transmembrane estrogen receptor, GPR30, are present in substantial concentration in IBC cells. The treatment with estradiol (E2), 4-hydroxytamoxifen, ICI 182,780, G1 and DPN led to a rapid activation of p-ERK1/2 implicating the involvement of ERα36 and GPR30 in non-genomic signaling pathway. This activation of p-ERK1/2 was confirmed through immunofluoresence staining. A dose dependent treatment of E2, 4-hydroxytamoxifen and DPN led to an equivalent activation of p-ERK1/2. We also found a substantial increase in SUM149 cell migration and invasiveness when the cells were treated with these ligands. The migration and invasion of SUM149 cells was dramatically reduced in the presence of MEK inhibitor U0126. We also investigated p-ERK1/2 immunostaining in IBC patient samples and found that three of five specimens used were positive. Thus the hormonal dependence of IBC is through a rapid non-genomic signaling, including the activation of p-ERK1/2, which might be mediated by a combination of estrogen receptors. This study not only explains the failure of traditional anti-estrogen therapies in IBC but also opens newer avenues for design of modified therapies targeting these estrogen receptors.
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Rangparia_gwu_0075M_10837.pdf | 2018-01-16 | Open Access |
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