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Zeynep Madak-Erdogan: ER-XPO1 crosstalk in tamoxifen resistance

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Dr. Madak-Erdogan, assistant professor of nutrition at the University of Illinois at Urbana-Champaign, talks about the research in an article she co-authored that is published in the October 2016 issue of the journal Molecular Endocrinology. The article focuses on finding therapeutic approaches to breast cancer that include novel, targetable, mechanism-based strategies by which the nuclear hormone estrogen receptor α (ERα) can be sensitized by endocrine therapies, specifically tamoxifen. ERα is present in approximately 70 percent of breast cancers and is considered one of the most critical predictive factors of breast cancer prognosis.

Hi my name is dana mother garden and i’m an assistant professor in food science and human nutrition department in university of illinois urbana-champaign my lab uses systems biology approach is to understand how nutrients and hormones impact breast cancer outcomes the vast majority of breast tumors in the clinic our poster for estrogen receptor-alpha while women

With these tumors typically respond well to endocrine therapies such as tamoxifen unfortunately almost half of the year alpha positive tumors will eventually require within 10 years nearly seventy percent of metastatic tumors are alpha positive and more women die each year from your alpha positive disease there are some available treatments for year alpha positive

Recurrent metastatic tumors such as combinations of endocrine therapy sun kinase inhibitors however they have been limited in an impact so the endocrine resistance remains a significant clinical problem and we need to identify novel targetable mechanism-based therapeutic strategies to improve the outcomes for women with your alpha positive recurrent tumors in

This study our overall objective is to investigate xp 0 1 which is a key nuclear export protein is a critical player and therapeutic target in endocrinology we have recently identified estrogen receptor-alpha is the key factor responsible for the activation and regulation of the subcellular localization of key kinase ah’s and based on this information we use the

Combinatorial approach in which we took advantage of tamoxifen sensitive and resistant cell culture models animal model and data from patient samples to delineate the role of nuclear transport pathways particularly xp 0 1 in tamoxifen sensitivity and induction therapy resistance we identified high levels of xp 1 which is the major nuclear exporter of the tumor

Suppressor proteins as a biomarker for tamoxifen resistance and we also evaluated this combined inhibition as the novel means to enhance the effectiveness of endocrine therapies using tamoxifen resistant mastana growth models we show that when we combined experiment and year alpha targeting agents this combination provided a quick effective and sustained tumor

Regression so our findings suggest that higher expression of selected nuclear export pathway proteins results in decreased residence times of important nuclear factors that would be involved in proper transcriptional responses to tamoxifen however when they are outside the nucleus they would confer resistance to tamoxifen and has exported the cytoplasm results in

Key proteins communicating with other components of the cancer cell machinery and also that would increase the aggressiveness of the cells so our results show that inhibition of nuclear export missionary would improve the therapy responsiveness and also delay the development of hormone targeted treatment resistance and recurrence

Transcribed from video
Zeynep Madak-Erdogan: ERα-XPO1 crosstalk in tamoxifen resistance By The Endocrine Society