Paclitaxel-induced transcriptional regulation of Fas signaling pathway is antagonized by dexamethasone.

Chemotherapy agents like paclitaxel are often a first line of therapy for triple-negative breast cancer patients and a last line of therapy for other aggressive breast cancers. While such agents are effective pro-apoptotic treatments for breast cancer cells, they produce many unwanted side effects. Synthetic glucocorticoids like dexamethasone are commonly prescribed during chemotherapy treatment of breast cancer patients for anti-emetic and anti-hypersensitivity purposes. Dexamethasone, however, is known to enhance cell survival in solid tumors. The prevalent use of dexamethasone in conjunction with paclitaxel in the treatment of breast cancer patients merits concern. Previous studies demonstrate dexamethasone-mediated survival in a subset of breast cancer cells in the presence of paclitaxel. This work expanded the types of cell lines studied and explored the molecular mechanism driving this phenotype. Human breast cancer cell lines representative of several subtypes of breast cancer including triple-negative breast cancer, luminal, and HER2 were treated in the presence and absence of paclitaxel, dexamethasone, and under co-treatment conditions. Cell survival was monitored under differing conditions. We then manipulated aspects of the nuclear factor kappa B (NFkappaB) signaling pathway to elucidate the importance of this pathway in overcoming chemotherapy treatment. All cell lines tested were sensitive to paclitaxel and showed dexamethasone-mediated rescue from paclitaxel-induced apoptosis, but the rescue of overall cell numbers was most pronounced in triple-negative breast cancer cell lines. Dexamethasone and paclitaxel inversely regulated the activity of NFkappaB, which is essential to both paclitaxel-mediated apoptosis and dexamethasone-mediated rescue. The transcriptional target of NFkappaB, Fas receptor, is inversely regulated by paclitaxel and dexamethasone and is a downstream target of paclitaxel-activated NFkappaB. Dexamethasone antagonizes paclitaxel-mediated apoptosis through inhibition of NFkappaB transcription of Fas receptor. Pre-treatment of breast cancer patients with dexamethasone may greatly reduce patient response to paclitaxel. Our study elucidates a novel mechanism of paclitaxel-induced apoptosis in breast cancer cell lines and explicates dexamethasone's antagonism of paclitaxel.

Frequently used antiemetic agent dexamethasone enhances the metastatic behaviour of select breast cancer cells.

Glucocorticoids, such as dexamethasone (Dex), are used to prevent common side effects induced by chemotherapy and are heavily prescribed for solid cancers such as breast cancer. There is substantial pre-clinical data to support that Dex activation of the glucocorticoid receptor overrides chemotherapy-induced apoptosis in breast cancer cell lines. These findings are compounded by a recent study demonstrating that increased glucocorticoid receptor activation by endogenous stress hormones increased breast cancer heterogeneity and metastasis. Our study is the first to use both in vitro and in vivo models to thoroughly compare the Dex response on the migration of multiple estrogen receptor negative (ER-) and ER+ cancer cell lines. ER+ and ER- breast cancer cell lines were studied to compare their endogenous glucocorticoid activity as well as their metastatic ability in response to Dex treatment. We show that in the ER- breast cancer lines, Dex increases cell numbers, invasiveness, and migration, while decreasing apoptotic ability. Furthermore, we show that following Dex treatment, ER- breast cancer lines migrate further in an in vivo zebrafish model in comparison to ER+ cell lines. The use of ROR1 antibody to block WNT signaling diminished the metastatic properties of ER- cells, however recombinant WNT5A alone was not sufficient to induce migration. Taken together, we demonstrate that Dex treatment exacerbates the metastatic potential of ER- but not ER+ cells. These findings add to the growing body of data stressing the potential adverse role of endogenous and synthetic glucocorticoids in breast cancer biology.