Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by the ovaries, while extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen after menopause. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. Several genetically modified mouse models have been generated to help understand the physiological and pathophysiological roles of aromatase and estrogen in the normal breast and in the development of breast cancers. Aromatase, the key enzyme for estrogen production, is comprised of at least ten partially tissue-selective and alternatively used promoters. These promoters are regulated by distinct signaling pathways to control aromatase expression and estrogen formation via recruitment of various transcription factors to their cis-regulatory elements. A shift in aromatase promoter use from I.4 to I.3/II is responsible for the excess estrogen production seen in fibroblasts surrounding malignant epithelial cells in breast cancers. Targeting these distinct pathways and/or transcription factors to modify aromatase activity may lead to the development of novel therapeutic remedies that inhibit estrogen production in a tissue-specific manner.

Members of the early growth response (Egr) gene family of transcription factors have nonredundant biological functions. Although Egr-3 is implicated primarily in neuromuscular development and immunity, its regulation and role in tissue repair and fibrosis has not been studied. We now show that in normal skin fibroblasts, Egr-3 was potently induced by transforming growth factor-β via canonical Smad3. Moreover, transient Egr-3 overexpression was sufficient to stimulate fibrotic gene expression, whereas deletion of Egr-3 resulted in substantially attenuated transforming growth factor-β responses. Genome-wide expression profiling in fibroblasts showed that genes associated with tissue remodeling and wound healing were prominently up-regulated by Egr-3. Notably, <5% of fibroblast genes regulated by Egr-1 or Egr-2 were found to be coregulated by Egr-3, revealing substantial functional divergence among these Egr family members. In a mouse model of scleroderma, development of dermal fibrosis was accompanied by accumulation of Egr-3-positive myofibroblasts in the lesional tissue. Moreover, skin biopsy samples from patients with scleroderma showed elevated Egr-3 levels in the dermis, and Egr-3 mRNA levels correlated with the extent of skin involvement. These results provide the first evidence that Egr-3, a functionally distinct member of the Egr family with potent effects on inflammation and immunity, is up-regulated in scleroderma and is necessary and sufficient for profibrotic responses, suggesting important and distinct roles in the pathogenesis of fibrosis.

Tumor dormancy is one of the stages in tumor development without clinical symptoms. Tumor dormant cells may appear in early stages of tumor development, as well as in micrometastasis and minimal residual disease. The mechanism for the switch of dormant cells between quiescent and proliferative stages is still largely unknown. Potential mechanisms that may account for the transition between dormant tumor cells and proliferative cells include angiogenesis, immune response, cellular factors, and signaling pathways. The clinical and therapeutic importance of dormant cells requires further studies to provide therapeutic strategies for inhibition of metastasis and tumor recurrence.

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Aromatase inhibitors (AIs) are the most effective endocrine treatment for estrogen receptor α-positive (ERα+) postmenopausal breast cancer. Identification of biomarkers that are able to predict AIs responsiveness of patients is a key for successful treatment. The currently used biomarkers for tamoxifen responsiveness, which including ERα as well as progesterone receptor can only predict part of the potential responders to AIs treatment. Sushi domain-containing protein 3 (SUSD3) is a potential novel biomarker of AIs responsiveness. The lack of SUSD3 expression in breast cancer tissue can be an important predictor for non-responsiveness to AI. Here we reviewed the property and function of SUSD3, its usage as a biomarker and the practicability for SUSD3 to become a target for immune therapy. We suggest this protein can be potentially measured or targeted for prevention, diagnostic, and therapeutic purposes for estrogen or progesterone-dependent disorders including breast cancer in women.

Pancreatic ductal adenocarcinoma (PDAC) is the 4 th leading cause of cancer-related deaths with high recurrence after surgery due to a paucity of effective post-surgical adjuvant treatments. DC-vaccines can activate multiple anti-tumor immune responses but have not been explored for PDAC treatment. No standard delivery route has also been established for DC vaccination, but intraperitoneal (IP) delivery is of particular interest because it allows increased DC-vaccine dosage and thus migration to draining lymph nodes. Here, we for the first time showed that IP delivery of DC-vaccines prior to tumor induction decreased tumor volume and prolonged survival in a PDAC mouse model. These approaches may be readily translated clinically for PDAC treatment as both DC vaccination and IP delivery are already used at the bedside for treatment or in clinical trials.

Although more than 1 in 4 men develop symptomatic inguinal hernia during their lifetime, the molecular mechanism behind inguinal hernia remains unknown. Here, we explored the protein-protein interaction network built on known inguinal hernia-causative genes to identify essential and common downstream proteins for inguinal hernia formation. We discovered that PIK3R1, PTPN11, TGFBR1, CDC42, SOS1, and KRAS were the most essential inguinal hernia-causative proteins and UBC, GRB2, CTNNB1, HSP90AA1, CBL, PLCG1, and CRK were listed as the most commonly-involved downstream proteins. In addition, the transmembrane receptor protein tyrosine kinase signaling pathway was the most frequently found inguinal hernia-related pathway. Our in silico approach was able to uncover a novel molecular mechanism underlying inguinal hernia formation by identifying inguinal herniarelated essential proteins and potential common downstream proteins of inguinal herniacausative proteins. OPEN ACCESSCitation: Mao Y, Chen L, Li J, Shangguan AJ, Kujawa S, Zhao H (2020) A network analysis revealed the essential and common downstream proteins related to inguinal hernia. PLoS ONE 15 (1): e0226885. https://doi.org/10.