A long non-coding RNA mediates the hormone responsiveness of during male urogenital development.

The novel long non-coding RNA (lncRNA) is extraordinarily conserved in both its location (syntenic with an essential gene in anogenital patterning) and sequence. Here we show that is upregulated following the testosterone surge from the developing testis and directly interacts with positively regulating its expression. expression is suppressed by estrogen, which in turn suppresses the expression of .

Impact of Chronic Multi-Generational Exposure to an Environmentally Relevant Atrazine Concentration on Testicular Development and Function in Mice.

A common herbicide, atrazine, is associated with poor health. Atrazine acts as an endocrine disruptor at supra-environmental levels. Little research, however, has been conducted regarding chronic exposure to environmental atrazine concentrations across generations.

Male germline development in the tammar wallaby, Macropus eugenii.

Male germ cells undergo two consecutive processes - pre-spermatogenesis and spermatogenesis - to generate mature sperm. In eutherian mammals, epigenetic information such as DNA methylation is dynamically reprogrammed during pre-spermatogenesis, before and during mitotic arrest. In mice, by the time germ cells resume mitosis, the majority of DNA methylation is reprogrammed.

Endocrine disrupting chemicals: Impacts on human fertility and fecundity during the peri-conception period.

It is becoming increasingly difficult to avoid exposure to man-made endocrine disrupting chemicals (EDCs) and environmental toxicants. This escalating yet constant exposure is postulated to partially explain the concurrent decline in human fertility that has occurred over the last 50 years. Controversy however remains as to whether associations exist, with conflicting findings commonly reported for all major EDC classes.

Mammary-specific ablation of Cyp24a1 inhibits development, reduces proliferation and increases sensitivity to vitamin D.

Active vitamin D (1,25(OH)2D) has been shown to regulate numerous cell processes in mammary cells. Degradation of 1,25(OH)2D is initiated by the mitochondrial enzyme, 25-hydroxyvitamin D 24-hydroxylase (CYP24 A1), and provides local control of 1,25(OH)2D bioactivity. Several reports of the association between elevated CYP24 A1 activity and breast cancer incidence, suggest that CYP24 A1 may be a target for therapeutic intervention.

Androgen Receptor Signalling Promotes a Luminal Phenotype in Mammary Epithelial Cells.

Androgens influence mammary gland development but the specific role of the androgen receptor (AR) in mammary function is largely unknown. We identified cell subsets that express AR in vivo and determined the effect of AR activation and transgenic AR inhibition on sub-populations of the normal mouse mammary epithelium by flow cytometry and immunohistochemistry. Immunolocalisation of AR with markers of lineage identity was also performed in human breast tissues.

Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion.

The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment.

Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer.

Alteration to the expression and activity of androgen receptor (AR) coregulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR coregulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer.

Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity.

Estrogen Receptor-β (ERβ) has been implicated in many cancers. In prostate and breast cancer its function is controversial, but genetic studies implicate a role in cancer progression. Much of the confusion around ERβ stems from antibodies that are inadequately validated, yet have become standard tools for deciphering its role.

Deciphering the divergent roles of progestogens in breast cancer.

Most breast cancers are driven by oestrogen receptor-α. Anti-oestrogenic drugs are the standard treatment for these breast cancers; however, treatment resistance is common, necessitating new therapeutic strategies. Recent preclinical and historical clinical studies support the use of progestogens to activate the progesterone receptor (PR) in breast cancers.

Pushing estrogen receptor around in breast cancer.

The estrogen receptor-α (herein called ER) is a nuclear sex steroid receptor (SSR) that is expressed in approximately 75% of breast cancers. Therapies that modulate ER action have substantially improved the survival of patients with ER-positive breast cancer, but resistance to treatment still remains a major clinical problem. Treating resistant breast cancer requires co-targeting of ER and alternate signalling pathways that contribute to resistance to improve the efficacy and benefit of currently available treatments.

Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17.

Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer.

Expression of androgen receptor splice variants in clinical breast cancers.

The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon.

Hormone-sensing mammary epithelial progenitors: emerging identity and hormonal regulation.

The hormone-sensing mammary epithelial cell (HS-MEC-expressing oestrogen receptor-alpha (ERα) and progesterone receptor (PGR)) is often represented as being terminally differentiated and lacking significant progenitor activity after puberty. Therefore while able to profoundly influence the proliferation and function of other MEC populations, HS-MECs are purported not to respond to sex hormone signals by engaging in significant cell proliferation during adulthood. This is a convenient and practical simplification that overshadows the sublime, and potentially critical, phenotypic plasticity found within the adult HS-MEC population.

Progesterone receptor modulates ERα action in breast cancer.

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome.

Bringing androgens up a NOTCH in breast cancer.

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development.

A survey of Sertoli cell differentiation in men after gonadotropin suppression and in testicular cancer.

It is widely held that the somatic cell population that is responsible for sperm development and output (Sertoli cells) is terminally differentiated and unmodifiable in adults. It is postulated, with little evidence, that Sertoli cells are not terminally differentiated in some phenotypes of infertility and testicular cancer. This study sought to compare markers of Sertoli cell differentiation in normospermic men, oligospermic men (undergoing gonadotropin suppression) and testicular carcinoma in situ (CIS) and seminoma samples.