A critical role for estrogen signaling in penis development.

Hypospadias, a developmental defect of the penis, is one of the most common congenital malformations in humans. Its incidence has rapidly increased over recent decades, and this has been largely attributed to our increased exposure to endocrine-disrupting chemicals. Penis development is primarily an androgen-driven process; however, estrogen and xenoestrogens are known to affect penis development in both humans and mice. Here, we investigated the role of estrogen in the developing penis. Using a novel penis culture system, we showed that exogenous estrogen directly targets the developing penis in utero to cause hypospadias. In addition, we also uncovered an unexpected endogenous role for estrogen in normal postnatal penis development and showed that a loss of estrogen signaling results in a mild hypospadias phenotype, the most common manifestation of this disease in humans. Our findings demonstrated that both androgen and estrogen signaling are intrinsically required for normal urethral closure. These findings confirmed that penis development is not an entirely androgen-driven process but one in which endogenous estrogen signaling also plays a critical role.-Govers, L. C., Phillips, T. R., Mattiske, D. M., Rashoo, N., Black, J. R., Sinclair, A., Baskin, L. S., Risbridger, G. P., Pask, A. J. A critical role for estrogen signaling in penis development.

Phenotypic Consequences of SLC25A40-ABCB1 Fusions beyond Drug Resistance in High-Grade Serous Ovarian Cancer.

Despite high response rates to initial chemotherapy, the majority of women diagnosed with High-Grade Serous Ovarian Cancer (HGSOC) ultimately develop drug resistance within 1-2 years of treatment. We previously identified the most common mechanism of acquired resistance in HGSOC to date, transcriptional fusions involving the ATP-binding cassette (ABC) transporter ABCB1, which has well established roles in multidrug resistance. However, the underlying biology of fusion-positive cells, as well as how clonal interactions between fusion-negative and positive populations influences proliferative fitness and therapeutic response remains unknown. Using a panel of fusion-negative and positive HGSOC single-cell clones, we demonstrate that in addition to mediating drug resistance, ABCB1 fusion-positive cells display impaired proliferative capacity, elevated oxidative metabolism, altered actin cellular morphology and an extracellular matrix/inflammatory enriched transcriptional profile. The co-culture of fusion-negative and positive populations had no effect on cellular proliferation but markedly altered drug sensitivity to doxorubicin, paclitaxel and cisplatin. Finally, high-throughput screening of 2907 FDA-approved compounds revealed 36 agents that induce equal cytotoxicity in both pure and mixed ABCB1 fusion populations. Collectively, our findings have unraveled the underlying biology of ABCB1 fusion-positive cells beyond drug resistance and identified novel therapeutic agents that may significantly improve the prognosis of relapsed HGSOC patients.

Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer.

ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.