Browsing by Subject "HER2"

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Alcohol promotes mammary tumor development through regulation of estrogen signaling
(2012-05) Wong, Amy W.; Nuñez, Nomelí P.
Breast cancer is the most common malignancy affecting women and the second leading cause of death among women in the United States. Alcohol consumption is one of the few modifiable risk factors for breast cancer development but the mechanism by which it contributes to mammary cancer development and progression remains unclear, although it has been suggested that estrogen is critical for this process. To determine if alcohol promotes mammary tumor development via the estrogen pathway, estrogen receptor alpha-negative (ER[alpha]-negative) MMTV-neu mice were treated with various doses of ethanol and activation of estrogen signaling was measured. Our results showed that alcohol consumption increased estrogen signaling activation, serum estrogen levels and, most interestingly, expression of ER[alpha] in tumor tissue in the ER[alpha]-negative mice. Several lines of evidence in literature suggest that ER[alpha] expression in ER[alpha]-negative cancer cells is inhibited through epigenetic regulation. Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than DNA sequence changes. Thus, to determine whether alcohol may regulate ER[alpha] re-expression in ER[alpha]-negative breast cancer cells through epigenetic mechanisms, we examined the effects of ethanol on CpG methylation and histone modifications (acetylation and methylation) of two ER[alpha]-negative breast cancer cell lines, MDA-MB-231 (human) and MMTV-neu (mouse). We also examined whether the epigenetic modifications subsequently affect the recruitment of transcriptional regulation complexes to the ER[alpha] promoter to regulate ER[alpha] transcription. Results showed that alcohol promotes ER[alpha] re-expression in these ER[alpha]-negative cell lines and that this effect was associated with decreased CpG methylation, an overall increase of histone acetylation and decrease of histone methylation, and an alteration in the enrichment of the ER[alpha] transcriptional regulation complexes (pRb2/p130-E2F4/5-HDAC1-SUV39H1-p300 and pRb2/p130-E2F4/5-HDAC1-SUV39H1-DNMT1) at the ER[alpha] promoter, which may contribute to cancer cell progression. In addition, we found that the inhibition of ER[alpha] by tamoxifen specifically blocks the effects of alcohol on ER[alpha] reactivation. To determine how alcohol promotes cell invasive ability, a critical process for cancer progression, we examined the role of two genes, metastasis suppressor Nm23 and integrin alpha-5 ITGA5, which we identified to be important for alcohol-induced breast cancer cell invasion. It has previously been shown that estrogen may regulate Nm23 expression and that estrogen regulation may be important for ITGA5-mediated cancer progression. Our results showed that alcohol promotes cancer cell invasion through the down-regulation of Nm23, which led to the subsequent increase of ITGA5 and increase of cell invasion. Collectively, data from my research strongly supports and provides evidence that alcohol promotes breast cancer development and progression through the regulation of estrogen signaling.
Characterizing treatment induced alterations of the tumor microenvironment towards optimizing therapeutic regimens in cancer
(2020-03-26) Bloom, Meghan Jean; Yankeelov, Thomas E.; Brock, Amy; Sorace, Anna G; Tunnell, James W; Virostko, Jack
It is well recognized that the tumor microenvironment plays a key role in cancer initiation, progression, and response to treatment. Therapies targeted towards the tumor microenvironment are being introduced in the clinic to be administered alongside chemotherapy and radiation, however, not every patient responds to treatment. The purpose of this dissertation is to characterize modulation of the tumor microenvironment induced by targeted therapies, and build a better understanding of how to exploit these alterations to increase efficacy of developing combination treatments. Our objective is addressed in three parts. First, we quantified temporal alterations in nuclear factor kappa B signaling and downstream gene expression to a small-molecule pathway inhibitor and demonstrated the complexity of altering pathway dynamics for therapeutic gain. Secondly, we characterized changes in innate immune cell infiltration in human epidermal growth factor receptor 2 positive (HER2+) breast cancer after targeted antibody treatment and identified mechanisms of vascular alterations and windows of reduced immune suppression. Lastly, we quantified the effects of radiation and targeted antibody therapy in HER2+ breast cancer and elucidated a potential to reduce radiation dose in this combination regimen. Collectively, the results presented provide valuable insight of how the tumor microenvironment can dictate treatment response and the potential to modulate the tumor microenvironment to enhance therapeutic efficacy