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Breast cancer is one of the leading causes contributing to the global cancer burden.The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immunooncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.

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The inflammatory tumor microenvironment has been implicated as a major player fueling tumor progression and an enabling characteristic of cancer, proline, glutamic acid, and leucine-rich protein 1 (PELP1) is a novel nuclear receptor coregulator that signals across diverse signaling networks, and its expression is altered in several cancers. However, investigations to find the role of PELP1 in inflammation-driven oncogenesis are limited. Molecular studies here, utilizing macrophage cell lines and animal models upon stimulation with lipopolysaccharide (LPS) or necrotic cells, showed that PELP1 is an inflammation-inducible gene. Studies on the PELP1 promoter and its mutant identified potential binding of c-Rel, an NF-κB transcription factor subunit, to PELP1 promoter upon LPS stimulation in macrophages. Recruitment of c-Rel onto the PELP1 promoter was validated by chromatin immunoprecipitation, further confirming LPS mediated PELP1 expression through c-Rel–specific transcriptional regulation. Macrophages that overexpress PELP1 induces granulocyte–macrophage colony-stimulating factor secretion, which mediates cancer progression in a paracrine manner. Results from preclinical studies with normal–inflammatory–tumor progression models demonstrated a progressive increase in the PELP1 expression, supporting this link between inflammation and cancer. In addition, animal studies demonstrated the connection of PELP1 in inflammation-directed cancer progression. Taken together, our findings provide the first report on c-Rel–specific transcriptional regulation of PELP1 in inflammation and possible granulocyte–macrophage colony-stimulating factor–mediated transformation potential of activated macrophages on epithelial cells in the inflammatory tumor microenvironment, reiterating the link between PELP1 and inflammation-induced oncogenesis. Understanding the regulatory mechanisms of PELP1 may help in designing better therapeutics to cure various inflammation-associated malignancies.

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BACKGROUND Endometrial carcinoma is a leading malignancy among females. Pre-operative imaging and biopsy are necessary to identify the disease. Clinicopathological analysis determines the extent of the disease. Complete surgical staging is advised for high-risk patients. The purpose of this study was to analyze the different clinical endpoints, prognostic factors and demographic details that will influence the survival patterns of the cases of carcinoma of endometrium who underwent surgery during the period from 2014 to 2017 at a tertiary care centre, Chennai, India. METHODS Patients diagnosed with operable endometrial carcinoma were surgically staged based on the surgical procedures performed namely, total abdominal hysterectomy (TAH) with bilateral salphingo-oophorectomy (BSO), bilateral pelvic lymph node dissection, and para-aortic lymphadenectomy (patients with high-risk features). Post-surgical staging specimens were histopathologically examined in the Department of Pathology. Adjuvant radiation was given to patients with stage IA grade II and above. Patients with stage III disease received adjuvant chemotherapy. Descriptive analysis was done to show the distributions of patients accordingly. Kaplan-Meier survival analysis was performed for the overall median survival of the patients. RESULTS The study consisted of a total of 35 patients with a mean age of 56 ± 8.64. Parameters such as age, clinicopathological features, stage (FIGO staging), tumor size, grade, lymphovascular invasion (LVI), myometrial invasion, cervical involvement, involvement of margins, lymph node ratio (LNR) and survival were studied. Tumor size and grade were found to be significant factors affecting the survival. Overall median survival period of patients who underwent surgery was found to be 31 months. CONCLUSIONS Tumor size and grade of the tumor are significant prognostic factors affecting the survival of the patients with carcinoma of endometrium. Lymph node ratio is a new concept in carcinoma endometrium to be pondered upon as a factor predicting survival in future studies thereby defining the role of lymph node dissection in surgical staging. KEYWORDS Endometrial Cancer, FIGO Staging, Lymph Node Ratio, Prognosis, Survival Analysis

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Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer.