Connexins: a junctional crossroad to breast cancer

El-Saghir, Jamal; El-Habre, Elia T.; El-Sabban, Marwan; Talhouk, Rabih

doi:10.1387/ijdb.113372je

Cited by 38 publications

(33 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Genes in the right hand quadrants are down 1.5-fold or more (P Ͻ 0.01) in the IR fl/fl Cre ϩ samples, whereas those in the left hand quadrants were up 1.5-fold or more (P Ͻ 0.01) in these samples. Data for each gene plotted is given in Supplemental Table 2 (11,46). that depends on increases in systemic levels of progesterone from the ovary and PRL from the pituitary (27); in this stage the number of cells increases exponentially as alveoli are formed and multiply.…”

Section: Discussionmentioning

confidence: 99%

The insulin receptor plays an important role in secretory differentiation in the mammary gland

Neville

Webb

Ramanathan

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Insulin is known to be an important regulator of milk secretion in the lactating mammary gland. Here we examine the role of insulin signaling in mammary development in pregnancy using a mouse with a floxed insulin receptor (IR) crossed with a mouse expressing Cre specifically in the mammary gland. In the mammary glands of these IR fl/fl Cre ϩ mice, expression of IR is significantly diminished throughout development. Glands from these mice had 50% fewer alveoli at midpregnancy; casein and lipid droplets were diminished by 60 and 75%, respectively, indicating a role for IR both in alveolar development and differentiation. In an acinar preparation from mammary epithelial cells (MEC) isolated from pregnant mice, insulin stimulated lumen formation, mammary cell size, acinar size, acinar casein content, and the formation of lipid droplets with a Km of ϳ1.7 nM. IGF-I and IGF-II had no effect at concentrations below 50 nM, and a function blocking antibody to the IGF type 1 receptor did not alter the response to insulin. We conclude that insulin interacting with IR is essential for mammary differentiation during murine pregnancy. Using array analysis, we then examined the expression of genes up-or downregulated Ͼ1.5-fold in the IR fl/fl Cre ϩ MECs, finding significant downregulation of differentiation specific genes and upregulation of cell cycle and extracellular matrix genes. We conclude that insulin fosters differentiation and may inhibit cell proliferation in the mammary gland of the midpregnant mouse. mammary development; acinar culture THE HORMONAL REGULATION OF mammary development and milk secretion has received extensive research attention in the last half-century (14), and the roles of the major sex steroid hormones, estrogen and progesterone (P4), as well as the lactogenic hormones prolactin (PRL) and hydrocortisone (HC) are quite well understood (26,28). Insulin is another story. It is difficult to ablate the insulin-secreting pancreatic islets, or to increase plasma insulin, without seriously impairing the metabolism of the whole animal; for this reason, alternative approaches have been necessary to elucidate the role of insulin in mammary gland development. The same concern extends to the use of transgenic and knockout mice that have been used to great effect to study steroid hormones. Although genetically modified mice can be used for studying the insulin system, as we will see the experimental design is crucial if complicating systemic effects are to be avoided.Much early data demonstrated a role for insulin in maintenance of milk secretion in the lactating animal (1,3,15,18,19,22,25,33,35). The earliest studies showed that insulin stimulated lipid synthesis in mammary slices from lactating ruminants (13). However, in these experiments, effects on mammary epithelial and adipose tissues were not distinguished. Furthermore, in the dairy cow, raising insulin levels from 0.25 to 1.3 nM in the context of glucose clamp experiments had no effect on milk production (21), suggesting that the lactating gland of the ...

show abstract

Section: Discussionmentioning

confidence: 99%

The insulin receptor plays an important role in secretory differentiation in the mammary gland

Neville

Webb

Ramanathan

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…A plethora of studies for the last several years have shown that connexins can modulate a cell's activity by interacting with key mediators of signaling pathways such as cytoskeletal proteins, enzymes, and signaling messengers [34, 35]. There is increasing evidence that gap junctions or connexins function as a signaling complex to regulate function and transformation of a single cell or group of neighboring cells in the environment [36]. …”

Section: Biophysical and Biochemical Properties Of Connexinsmentioning

confidence: 99%

Connexin’s Connection in Breast Cancer Growth and Progression

Banerjee

2016

International Journal of Cell Biology

View full text Add to dashboard Cite

Gap junctions are cell-to-cell junctions that are located in the basolateral surface of two adjoining cells. A gap junction channel is composed of a family of proteins called connexins. Gap junction channels maintain intercellular communication between two cells through the exchange of ions, small metabolites, and electrical signals. Gap junction channels or connexins are widespread in terms of their expression and function in maintaining the development, differentiation, and homeostasis of vertebrate tissues. Gap junction connexins play a major role in maintaining intercellular communication among different cell types of normal mammary gland for proper development and homeostasis. Connexins have also been implicated in the pathogenesis of breast cancer. Differential expression pattern of connexins and their gap junction dependent or independent functions provide pivotal cross talk of breast tumor cells with the surrounding stromal cell in the microenvironment. Substantial research from the last 20 years has accumulated ample evidences that allow us a better understanding of the roles that connexins play in the tumorigenesis of primary breast tumor and its metastatic progression. This review will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease.

show abstract

“…However, as yet, there are no epidemiology studies to determine whether female patients harboring a subclass of loss-of-function or gain-of-function Cx26 mutants have any breast defects as the data set is difficult to ascertain. In addition, both Cx43 and Cx26 are implicated in other breast-related diseases such as cancer, which has previously been reviewed by El-Saghir et al (2011), although it remains unclear whether patients with loss-of-function mutations in the genes that encode Cx43 or Cx26 are predisposed (Naus & Laird 2010). Ultimately, our understanding of the role of gap junction proteins in normal breast physiology will provide future insights into the pathologies of the breast and the possible development of targeted therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Insights into the role of connexins in mammary gland morphogenesis and function

2015

View full text Add to dashboard Cite

Gap junctions formed of connexin subunits link adjacent cells by direct intercellular communication that is essential for normal tissue homeostasis in the mammary gland. The mammary gland undergoes immense remodeling and requires exquisite regulation to control the proliferative, differentiating, and cell death mechanisms regulating gland development and function. The generation of novel genetically modified mice with reduced or ablated connexin function within the mammary gland has advanced our understanding of the role of gap junctions during the complex and dynamic process of mammary gland development. These studies have revealed an important stagespecific role for Cx26 (GJA1) and Cx43 (GJB2), while Cx30 (GJB6) and Cx32 (Gjb1) can be eliminated without compromising the gland. Yet, there remain gaps in our understanding of the role of mammary gland gap junctions.Reproduction (2015) 149 R279-R290

show abstract

Connexins: a junctional crossroad to breast cancer

Cited by 38 publications

References 46 publications

The insulin receptor plays an important role in secretory differentiation in the mammary gland

The insulin receptor plays an important role in secretory differentiation in the mammary gland

Connexin’s Connection in Breast Cancer Growth and Progression

Insights into the role of connexins in mammary gland morphogenesis and function

Contact Info

Product

Resources

About