The Breast Cancer Susceptibility Genes, BRCA1 and BRCA2, are the dynamic regulators of genomic integrity. Inherited mutations in these genes are associated with the development of cancer in multiple organs including the breast and ovary. Mutations of BRCA1/2 genes greatly increase lifetime risk to develop breast and ovarian cancer and these mutations are frequently observed in hereditary breast and ovarian cancers. In addition, misregulation and altered expressions of BRCA1/2 proteins potentiate sporadic forms of breast cancer. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Thus, deficiencies of BRCA1/2 functions lead to the accumulation of genetic alterations and ultimately influence the development of cancer. Studies since identification of both BRCA1 and BRCA2 have provided strong evidences for their tumor suppressor activities specifically for breast and ovarian cancer and this article aims to review the current state of knowledge regarding the BRCAs and associated cancer risk.

GATA transcription factors are implicated in establishing cell fate during mammalian development. In early mammalian embryos, GATA3 is selectively expressed in the extraembryonic trophoblast lineage and regulates gene expression to promote trophoblast fate. However, trophoblast-specific GATA3 function is dispensable for early mammalian development. Here, using dual conditional knockout mice, we show that genetic redundancy of Gata3 with paralog Gata2 in trophoblast progenitors ensures the successful progression of both pre- and postimplantation mammalian development. Stage-specific gene deletion in trophoblasts reveals that loss of both GATA genes, but not either alone, leads to embryonic lethality prior to the onset of their expression within the embryo proper. Using ChIP-seq and RNA-seq analyses, we define the global targets of GATA2/GATA3 and show that they directly regulate a large number of common genes to orchestrate stem versus differentiated trophoblast fate. In trophoblast progenitors, GATA factors directly regulate BMP4, Nodal and Wnt signaling components that promote embryonic-extraembryonic signaling cross-talk, which is essential for the development of the embryo proper. Our study provides genetic evidence that impairment of trophoblast-specific GATA2/GATA3 function could lead to early pregnancy failure.

The first mammalian cell lineage commitment is the formation of the trophectoderm (TE) and the inner cell mass (ICM) lineages during preimplantation development. Proper development of the TE and ICM lineages is dependent upon establishment of specific transcriptional programs. However, the epigenetic mechanisms that functionally contribute to establish TE-and ICM-specific transcriptional programs are poorly understood. Here, we show that proper development of the TE and ICM lineages is coordinated via combinatorial regulation of embryonic ectoderm development (EED) and lysinespecific demethylase 6B (KDM6B). During blastocyst formation, the relative levels of EED and KDM6B expression determine altered polycomb repressor 2 (PRC2) complex recruitment and incorporation of the repressive histone H3 lysine 27 trimethylation (H3K27Me3) mark at the chromatin domains of TE-specific master regulators CDX2 and GATA3, leading to their activation in the TE lineage and repression in the ICM lineage. Furthermore, ectopic gain of EED along with depletion of KDM6B in preimplantation mouse embryos abrogates CDX2 and GATA3 expression in the nascent TE lineage. The loss of CDX2 and GATA3 in the nascent TE lineage results in improper TE development, leading to failure in embryo implantation to the uterus. Our study delineates a novel epigenetic mechanism that orchestrates proper development of the first mammalian cell lineages. Successful reproduction in placental mammals requires proper specification of the trophectoderm (TE) and the inner cell mass (ICM) lineages in preimplantation embryos. The ICM develops to the embryo proper, whereas the TE is essential for embryo implantation to the uterus and the origin of trophoblast cells of the placenta. During preimplantation mouse development, beginning at the 8-cell stage, blastomeres are polarized and allocated to inside and outside positions. During subsequent development, distinct transcriptional programs ensure the commitment of outside cells to the TE lineage and the inside cells to the ICM lineage (1-4). The TE is crucial for embryo implantation and develops into parts of the placenta. Improper TE specification results in either impaired preimplantation development or defective embryo implantation (5-8), which are the leading causes of infertility and early pregnancy failure.Several key transcription factors, like CDX2 and GATA3, have been implicated in proper development of the TE lineage (9-11). Gene-knockout studies in mice showed that another transcription factor, TEAD4, is essential for the establishment of the TE-specific transcriptional program and maturation of embryos to the blastocyst stage (12, 13). Interestingly, these key TE regulators have dynamic expression patterns during the course of preimplantation development. For example, transcription factors CDX2 and GATA3 are ubiquitously expressed in the blastomeres of an 8-cell mouse embryo. However, upon cell polarization, they are predominantly expressed in the outside cells (9,14). This pattern is maintained at the bla...

Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCk/i, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCk/i signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCk/i signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCk/i expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCk/i significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCk/i-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFb and IL1b could activate PKCk/i signaling in TNBC cells and depletion of PKCk/i impairs NF-jB p65 (RelA) nuclear localization. We observed that cytokine-PKCk/i-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCk/i promote TNBC growth, invasion and metastasis. Thus, targeting PKCk/i signaling could be a therapeutic option for breast cancer, including the TNBC subtype.