Impairment of Uterine Contractility Is Associated with Unexplained Infertility
SEMINARS IN REPRODUCTIVE MEDICINE
Authors: Hunt, Sarah; Abdallah, Karim S.; Ng, Ernest; Rombauts, Luk; Vollenhoven, Beverley; Mol, Ben W.
The uterine junctional zone represents the juncture between endometrium and myometrium. The junctional zone is hormonally dependent and displays continuous peristaltic activity throughout the menstrual cycle in the nonpregnant state which is concerned with sperm transport and embryo implantation. Peristalsis may be observed using various invasive and noninvasive modalities, of which ultrasound is the most readily applied in the clinical setting. Women with pelvic pathology display alterations in uterine peristalsis which may contribute to infertility. Characterization of peristalsis in infertility subgroups, the development of a subjective peristalsis tool, and the application of potential therapeutics to an assisted reproductive treatment setting are the subject of ongoing investigation. Meta-analysis indicates a potential role for oxytocin antagonist in the improvement of fertility treatments.
Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer
CELL DEATH & DISEASE
Authors: Charan, Manish; Das, Subhadip; Mishra, Sanjay; Chatterjee, Nabanita; Varikuti, Sanjay; Kaul, Kirti; Misri, Swati; Ahirwar, Dinesh K.; Satoskar, Abhay R.; Ganju, Ramesh K.
Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.