Androgen receptor: Structure, signaling, function and potential drug discovery biomarker in different breast cancer subtypes.

The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy worldwide. >70 % of AR expression in primary and metastatic breast tumors has been observed which suggests that AR may be a new marker and a potential therapeutic target among AR-positive BC patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. Downstream signaling of AR might also affect many clinically important pathways that are emerging as clinical targets in BC. AR exhibits different behaviors depending on the breast cancer molecular subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since AR positivity's prognostic and predictive value remains uncertain, it is difficult to identify and stratify patients who would benefit from AR-targeted therapies alone. Thus, the need of the hour is to target the androgen receptor as a monotherapy or in combination with other conventional therapies which has proven to be an effective clinical strategy for the treatment of prostate cancer patients, and these therapeutic strategies are increasingly being investigated in breast cancer. Therefore, in this manuscript, we review the role of AR in various cellular processes that promote tumorigenesis and aggressiveness, in different subtypes of breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of breast cancer.

Localized delivery of Erlotinib using liposomal gel formulations for the treatment of oral squamous cell carcinoma.

Oral cancer accounts for more than 350,000 cases worldwide with 90% of them being oral squamous cell carcinomas (OSCC). The current treatment modalities of chemoradiation have poor outcomes along with harmful effects to neighbouring healthy tissues. The present study aimed to deliver Erlotinib (ERB), locally at the site of tumor arising in the oral cavity. ERB was encapsulated in liposomal formulations (ERB Lipo) and optimized using full factorial, 32 experimental design. The optimized batch was then coated with chitosan to obtain CS-ERB Lipo and were characterized further. Both liposomal ERB formulations had size <200 nm and PDI < 0.4. Zeta potential was upto -50 mV for ERB Lipo and upto +25 mV for CS-ERB Lipo indicating stable formulation. Liposomal formulations were freeze dried and loaded into gel to study in-vitro release and chemotherapeutic evaluation. CS-ERB Lipo showed sustained release upto 36 h from gel as compared to control formulation. In-vitro cell viability studies showed potent anti-cancer activity on KB-cells. In-vivo studies showed better pharmacological efficacy in terms of tumor volume reduction for ERB Lipo gel (49.19%) and CS-ERB Lipo gel (55.27%) as compared to plain ERB Gel (38.88%) applied locally. Histology also revealed that formulation could alleviate dysplasia condition to hyperplasia. The locoregional therapy of ERB Lipo gel and CS-ERB Lipo gel thus show promising outcome in improving pre-malignant and early-stage oral cavity cancers.

Integrating mental health into climate change education to inspire climate action while safeguarding mental health.

Climate change is the greatest threat humanity faces, and puts at risk the mental health and wellbeing of children and young people. Climate change education must equip children and young people with the knowledge, skills and resilience to live in an uncertain future, sustainably take relevant climate action and work in climate careers. As attention on climate change education grows, this is a critical moment for the mental health community to ensure mental health and wellbeing considerations are embedded. Critically, appropriate integration of mental health can enable these very necessary goals of equipping children and young people to live and work in a future where climate change looms large. This paper explores why promoting good mental health and wellbeing and building psychological resilience can help achieve climate change education outcomes, and why not doing so risks harming children and young people's mental health. It also explores how integrating discussions about emotions, mental health, and coping strategies within climate change education can be a route into wider discussions about mental health, to support children and young people in the context of rising mental health needs. Learning from an existing approach to promoting good mental health and wellbeing in schools (the 'whole school approach') provides the opportunity to explore one avenue through which such an integrated approach could be implemented in practice. Identifying appropriate mechanisms to integrate mental health into climate change education will require co-design and research with educators and young people, and addressing systemic barriers facing the schools sector.

TGF-ß at the crossroads of multiple prognosis in breast cancer, and beyond.

Transforming growth factor ß (TGF-ß), a pluripotent cytokine and a multifunctional growth factor has a crucial role in varied biological mechanisms like invasion, migration, epithelial-mesenchymal transition, apoptosis, wound healing, and immunosuppression. Moreover, it also has an imperative role both in normal mammary gland development as well as breast carcinogenesis. TGF-ß has shown to have a paradoxical role in breast carcinogenesis, by transitioning from a growth inhibitor to a growth promoter with the disease advancement. The inter-communication and crosstalk of TGF-ß with different signaling pathways has strengthened the likelihood to explore it as a comprehensive biomarker. In the last two decades, TGF-ß has been studied extensively and has been found to be a promising biomarker for early detection, disease monitoring, treatment selection, and tumor progression making it beneficial for disease management. In this review, we focus on the signaling pathways and biological activities of the TGF-ß family in breast cancer pathogenesis and its role as a circulatory and independent biomarker for breast cancer progression and metastasis. Moreover, this review highlights TGF-ß as a drug target, and the underlying mechanisms through which it is involved in tumorigenesis that will aid in the development of varied therapies targeting the different stages of breast cancer.

Prognostic utility of circulating transforming growth factor beta 1 in breast cancer patients.

Transforming growth factor betas (TGF-ßs) are multifunctional cytokines with a biphasic role in breast tumorigenesis, acting as tumor suppressors at early stages while stimulating tumor progression at later stages (TGF-ß switch). Among the 3 human isoforms, TGF-ß1 is known to be overexpressed in several tumor types including breast tumors. TGF-ß signaling and "crosstalk" in the tumor microenvironment presents a unique challenge and an opportunity to develop novel therapies. We assessed circulating TGF-ß1 levels by ELISA in blood samples from 117 previously untreated breast cancer patients in this prospective study to explore the TGF-ß switch at the forefront. The levels were correlated with clinicopathological prognosticators like age, menopausal status, nodal status, histological type, histological grade, necrosis, stromal involvement, and survival. Higher mean preoperative serum TGF-ß1 was observed in early-stage patients than controls (p=0.05) as revealed by receiver operating characteristic (ROC) analysis. Elevation of TGF-ß1 was evident in patients with advanced-stage breast cancer compared with those having early-stage disease (p=0.0001). Prognosticators of an aggressive phenotype were associated with higher TGF-ß1 levels, and higher levels thus announced the likelihood of relapse, marking the role of TGF-ß1 as a tumor promoter and evidencing the existence of a TGF-ß switch. Moreover, higher levels of TGF-ß1 shortened the overall survival in breast cancer patients (p=0.010). The results indicate that circulating TGF-ß1 may be used as a predictive and prognostic marker in breast carcinoma.

Transforming growth factor beta 2: a predictive marker for breast cancer.

Dual role of TGF-beta signaling in breast tumorigenesis as an inhibitor in early stages and promoter in advanced stages has been well established and known as TGF-beta switch. However, the biological mechanisms needs to be explored. Aim of the present study was to look for the usefulness of TGF-beta as a predictive marker for breast cancer and to offer a better predictability to identify patients likely to benefit from antiTGF-beta strategies. Circulatory as well as transcript levels of TGF-beta2 were estimated from 118 pretherapeutic breast cancer patients using ELISA and q-PCR with ddCt method. Multifactorial analysis was performed to correlate the results to clinico-pathological prognosticators and Kaplan-Meier survival analysis with a median follow-up of 49 months was also evaluated. Circulating TGF-beta2 was similar in control and breast cancer patients. TGF-beta2 was significantly upregulated in advanced tumors compared to early tumors. An inverse correlation was observed between TGF-beta2 protein and mRNA; nevertheless both exhibited significant correlations with clinico-pathological prognosticators. Higher expression of TGF-beta2 mRNA was connected to an early relapse in advanced stage than early stage patients. It is the first report to evaluate circulatory and transcript levels exhibiting TGF-beta switch and confirming the utility of TGF-beta2 as an important predictive marker for breast cancer.