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Ganju, R. K.

Publications and source records attributed to Ganju, R. K..

2 recordsLinked to original sources
bioRxiv2022

Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer

BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor positive (ER+) breast cancer accounts for 70% of all breast cancer subtypes. Although ER+ breast cancer initially responds to estrogen deprivation or blockade, resistance emergence compelling the use of more aggressive therapies. While ER is a driver in ER+ breast cancer, ER{beta} plays an inhibitory role in several different cancer types. To date, the lack of highly selective ER{beta} agonists without ER activity has limited the exploration of ER{beta} activation as a strategy for ER+ breast cancer. MethodsWe measured expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ER+ breast cancer cell lines upon treatments with specific ER{beta} agonists, including OSU-ERb-12 and LY500307 was assessed. The specificity of the ER{beta} agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of the agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ER+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2 regulated genes. ResultsIn this study, we demonstrate the efficacy of highly selective ER{beta} agonists in ER+ breast cancer cell lines and drug-resistant derivatives. ER{beta} agonists blocked cell proliferation, migration and colony formation; and induced apoptosis and S and/or G2/M cell cycle arrest of ER+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ER{beta} agonists and ER antagonists suggested that the efficacy of ER{beta} agonists is maximized by combination with ER blockade. Lastly, ESR2 (ER{beta} gene) expression was negatively correlated with ESR1 (ER gene) and CCND1 RNA expression in human metastatic ER+/HER2-breast cancer samples. ConclusionOur results demonstrate that highly selective ER{beta} agonists attenuate the viability of ER+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ER+ breast cancer.

cancer biology↗
bioRxiv2022

Augmentation of extracellular ATP synergizes with chemotherapy in triple negative breast cancer

IntroductionBreast cancer affects two million women worldwide every year and is the most common cause of cancer-related death among women. The triple-negative breast cancer (TNBC) sub-type is associated with an especially poor prognosis because currently available therapies, fail to induce long-lasting responses. Therefore, there is an urgent need to develop novel therapies that result in durable responses. One universal characteristic of the tumor microenvironment is a markedly elevated concentration of extracellular adenosine triphosphate (eATP). Chemotherapy exposure results in further increases in eATP through its release into the extracellular space of cancer cells via P2RX channels. eATP levels are reduced by eATPases. Given that high concentrations of eATP are cytotoxic, we hypothesized that augmenting the release of eATP through P2RX channels and inhibiting extracellular ATPases would sensitize TNBC cells to chemotherapy. MethodsTNBC cell lines MDA-MB 231, Hs 578t and MDA-MB 468 and non-tumorigenic immortalized mammary epithelial MCF-10A cells were treated with increasing concentrations the chemotherapeutic agent paclitaxel in the presence of eATPase inhibitors, specific agonists or antagonists of P2RXs with cell viability and eATP content being measured. Additionally, the mRNA, protein and cell surface expressions of the purinergic receptors P2RX4 and P2RX7 were evaluated in all examined cell lines via qRT-PCR, western blot, and flow cytometry analyses, respectively. ResultsIn the present study, we observed dose-dependent declines in cell viability and increases in eATP in paclitaxel-treated TNBC cell lines in the presence of inhibitors of eATPases. These effects were reversed by specific antagonists of P2RXs. Similar results were observed with P2RX activators. All examined cell lines expressed both P2RX4 and P2RX7 at the mRNA, protein and cell surface levels. ConclusionThese results reveal that eATP modulates the chemotherapeutic response in TNBC cell lines which could be exploited to enhance the efficacy of chemotherapy regimens for TNBC.

cancer biology↗