Several studies have made strong efforts to understand how age and parity modulate the risk of breast cancer. A holistic understanding of the dynamic regulation of the morphological, cellular, and molecular milieu of the mammary gland offers insights into the drivers of breast cancer development as well as into potential prophylactic interventions, the latter being a longstanding ambition of the research and clinical community aspiring to eradicate the disease. In this review we discuss mechanisms that react to pregnancy signals, and we delineate the nuances of pregnancyassociated dynamism that contribute towards either breast cancer development or prevention. Further definition of the molecular basis of parity and breast cancer risk may allow the elaboration of tools to predict and survey those who are at risk of breast cancer development. Parity: A Perspective for Therapeutic and Prophylactic InterventionBreast cancer is the most frequently diagnosed malignance in women. It strikes >1.6 million women worldwide, and about one in eight 8 women in the USA will develop breast cancer in their lifetime (Box 1 and Table 1). Most breast cancers arise because of dysfunction of cells in mammary ducts (50-70% of tumors) or lobules (10-15% of breast cancers), which categorizes these tumors as carcinomas, specifically adenocarcinomas. Some breast tumors are sarcomas, originating in the stroma or muscle. Other types and subtypes of breast cancer are less frequent, and a single diagnosis of breast cancer may refer to a combination of different tumors (www.breastcancer.org) (Box 1).Parity is known to have a dual effect on breast cancer risk. In many ways, breast tumorigenesis mimics several mechanisms that are commonly activated during pregnancy, including augmented cell proliferation, alterations in cell shedding, reduced cell apoptosis, altered gene expression, and extracellular matrix (ECM) modifications. On the other hand, epidemiological studies have provided evidence of the cancer-preventive benefits of pregnancy wherein an early age of pregnancy decreases the risk of breast cancer development. Although understanding the molecular mechanisms underlying these phenomena is still in its infancy, their elucidation will open new avenues to target breast cancer. Mammary Gland Composition and DevelopmentThe mammary gland is a complex and highly adaptive organ whose main function, in female mammals, is to produce milk during lactation for the sustenance of young offspring. The gland is composed of a variety of cell types, including fibroblasts, adipocytes, epithelial, endothelial, and immune cells. The epithelial cells can be further subdivided into multiple cell types that, together, form the branching structure of the gland and constitute the secretory alveoli during lactation. Two main epithelial cell compartments can be distinguished in the mammary gland: the luminal compartment [the inner cell layer, localized between the lumen (see Glossary),and the basal compartment] and the basal compartment (the outer layer surrounding ...

Background Members of the family of NEK protein kinases (NIMA-related kinases) were described to have crucial roles in regulating different aspects of the cell cycle. NEK10 was reported to take part in the maintenance of the G2/M checkpoint after exposure to ultraviolet light. NEK1, NEK5, NEK2 and NEK4 proteins on the other hand have been linked to mitochondrial functions. Methods HEK293T cells were transfected with FLAG empty vector or FLAG-NEK10 and treated or not with Zeocin. For proteomic analysis, proteins co-precipitated with the FLAG constructs were digested by trypsin, and then analyzed via LC-MS/MS. Proteomic data retrieved were next submitted to Integrated Interactome System analysis and differentially expressed proteins were attributed to Gene Ontology biological processes and assembled in protein networks by Cytoscape. For functional, cellular and molecular analyses two stable Nek10 silenced HeLa cell clones were established. Results Here, we discovered the following possible new NEK10 protein interactors, related to mitochondrial functions: SIRT3, ATAD3A, ATAD3B, and OAT. After zeocin treatment, the spectrum of mitochondrial interactors increased by the proteins: FKBP4, TXN, PFDN2, ATAD3B, MRPL12, ATP5J, DUT, YWHAE, CS, SIRT3, HSPA9, PDHB, GLUD1, DDX3X, and APEX1. We confirmed the interaction of NEK10 and GLUD1 by proximity ligation assay and confocal microscopy. Furthermore, we demonstrated that NEK10-depleted cells showed more fragmented mitochondria compared to the control cells. The knock down of NEK10 resulted further in changes in mitochondrial reactive oxygen species (ROS) levels, decreased citrate synthase activity, and culminated in inhibition of mitochondrial respiration, affecting particularly ATP-linked oxygen consumption rate and spare capacity. NEK10 depletion also decreased the ratio of mtDNA amplification, possibly due to DNA damage. However, the total mtDNA content increased, suggesting that NEK10 may be involved in the control of mtDNA content. Conclusions Taken together these data place NEK10 as a novel regulatory player in mitochondrial homeostasis and energy metabolism.

SummaryChromatin remodeling is a key requirement for transcriptional control of cellular differentiation. However, the factors that alter chromatin architecture in mammary stem cells (MaSCs) are poorly understood. Here, we show that BPTF, the largest subunit of the NURF chromatin remodeling complex, is essential for MaSC self-renewal and differentiation of mammary epithelial cells (MECs). BPTF depletion arrests cells at a previously undefined stage of epithelial differentiation that is associated with an incapacity to achieve the luminal cell fate. Moreover, genome-wide analysis of DNA accessibility following genetic or chemical inhibition, suggests a role for BPTF in maintaining the open chromatin landscape at enhancers regions in MECs. Collectively, our study implicates BPTF in maintaining the unique epigenetic state of MaSCs.