Background/Aim GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Materials and Methods Transgenic mice, 3D cultures and xenografts were used to examine the effect of mutant GATA3 expression on mammary cell proliferation. Results Mutant GATA3 accelerated tumor growth of ZR751 cell xenografts and promoted precocious lobuloalveolar development in transgenic mouse mammary glands. Conclusion These data indicate that the GATA3 mutations, recently observed in breast cancer, encode active transcription factors, which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of ER-positive breast cancer cell lines.

Glycogen debranching enzyme (AGL) and Glycogen phosphorylase (PYG) are responsible for glycogen breakdown. We have earlier shown that AGL is a regulator of bladder tumor growth. Here we investigate the role of AGL in non-small cell lung cancers (NSCLC). Short hairpin RNA (shRNA) driven knockdown of AGL resulted in increased anchorage independent and xenograft growth of NSCLC cells. We further establish that an increase in hyaluronic acid (HA) synthesis driven by Hyaluronic Acid Synthase 2 (HAS2) is critical for anchorage independent growth of NSCLC cells with AGL loss. Using gene knockdown approach against HAS2 and by using 4-methylumbelliferone (4MU), an inhibitor of HA synthesis, we show that HA synthesis is critical for growth of NSCLC cells that have lost AGL. We further show NSCLC cells without AGL expression are dependent on RHAMM for HA signaling and growth. Analysis of NSCLC patient datasets established that patients with low AGL/high HAS2 or low AGL/high RHAMM mRNA expression have poor overall survival compared to patients with high AGL/low HAS2 or high AGL/low RHAMM expression. We show for the first time that loss of AGL promotes anchorage independent growth of NSCLC cells. We further show that HAS2 driven HA synthesis and signaling via RHAMM is critical in regulating growth of these cancer cells with AGL loss. Further patients presenting with low AGL and HAS2 or RHAMM over expressing tumors might present the ideal cohort who would respond to inhibitors of HA synthesis and signaling.

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BackgroundWe present a rare case where distant metastasis of a low grade bladder tumor was observed. We carried out detailed genomic analysis and cell based experiments on patient tumor samples to study tumor evolution, possible cause of disease and provide personalized treatment strategies.Case presentationA man with a smoking history was diagnosed with a low-grade urothelial carcinoma of the bladder and a concurrent high-grade upper urinary tract tumor. Seven years later he had a lung metastasis. We carried out exome sequencing on all the patient’s tumors and peripheral blood (germline) to identify somatic variants. We constructed a phylogenetic tree to capture how the tumors are related and to identify somatic changes important for metastasis. Although distant metastasis of low-grade bladder tumor is rare, the somatic variants in the tumors and the phylogenetic tree showed that the metastasized tumor had a mutational profile most similar to the low grade urothelial carcinoma. The primary and the metastatic tumors shared several important mutations, including in the KMT2D and the RXRA genes. The metastatic tumor also had an activating MTOR mutation, which may be important for tumor metastasis. We developed a mutational signature to understand the biologic processes responsible for tumor development. The mutational signature suggests that the tumor mutations are associated with tobacco carcinogen exposure, which is concordant with the patient’s smoking history. We cultured cells from the lung metastasis to examine proliferation and signaling mechanisms in response to treatment. The mTOR inhibitor Everolimus inhibited downstream mTOR signaling and induced cytotoxicity in the metastatic tumor cells.ConclusionWe used genomic analysis to examine a rare case of low grade bladder tumor metastasis to distant organ (lung). Our analysis also revealed exposure to carcinogens found is tobacco as a possible cause in tumor development. We further validated that the patient might benefit from mTOR inhibition as a potential salvage therapy in an adjuvant or recurrent disease setting.Electronic supplementary materialThe online version of this article (10.1186/s12894-018-0386-8) contains supplementary material, which is available to authorized users.

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