The nuclear factor kappa b (NFkb) plays a critical role in the development of antiestrogen resistance

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Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. Resistance to endocrine therapies remains a major problem in the management of estrogen receptor (ER) positive breast cancer. Precise mechanisms that contribute to acquired resistance remain undefined. While over-expression of nuclear transcription factor-kB (NFkB) has been implicated in drug resistance, its role in affecting responsiveness to antiestrogens (TAM and ICI 182,780; Faslodex) is unknown. We show here that inhibition of NFkB either by over-expression of a mutant IkB"super-repressor" (IkBSR) or a small molecule inhibitor (parthenolide) provides a means to overcome resistance to both SERMs (4-hydroxytamoxifen; 4HT) and SERDs (ICI 182,780). Parthenolide not only reverses resistance to antiestrogens in resistant cells (MCF7/LCC9; MCF7/RR) but also increases the responsiveness of sensitive cells (MCF-7; MCF7/LCC1) to both SERMs and SERDs. These effects are independent of changes in the level of autophagy, measured by cleavage of LC3 or inhibition of p62/SQSTM1 expression, or in cell cycle distribution.; We then proceed to show that treatment with 4HT in the presence of an inhibited NFkB restores TAM-induced cell death in resistant cells by decreasing the expression of BCL2 (anti-apoptotic protein), increasing mitochondrial membrane permeability (MMP), and inducing apoptosis. These activities of NFkB involve the regulation of CASP8 action upstream of mitochondria. The pancaspase inhibitor (PI) and a specific CASP8 inhibitor (C8I), both reverse the effects of IkBSR and parthenolide on BCL2 expression, MMP, and responsiveness to 4HT. In addition to establishing a role for NFkB in the development of antiestrogen resistant phenotype, we provide evidence that NFkB activation in resistant cells is necessary but not sufficient to drive their antiestrogen resistant phenotype.; Taken together, these data show that parthenolide acts primarily through its inhibition of NFkB, providing important and relevant new insights into how NFkB signaling affects antiestrogen (primarily tamoxifen; TAM) responsiveness in breast cancer cells. These data also strongly suggest that a combination of parthenolide and SERM/SERD may offer a novel therapeutic approach to the management of some ER+ breast cancers. In this era of personalized medicine, measuring NFkB and markers of its functional signaling may help us to tailor specific therapies to individual breast cancer patients while improving prognosis and clinical outcomes for women.
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