Effects of menopausal hormonal therapy on occult breast tumors

Authors

Richard J. Santen, Yan Song, Wei Yue, Ji-Ping Wang, Daniel F. Heitjan

Abstract

An estimated 7% of 40–80 year old women dying of unrelated causes harbor occult breast tumors at autopsy. These lesions are too small to be detected by mammography, a method which requires tumors to be approximately 1 cm in diameter to be diagnosed. Tumor growth rates, as assessed by “effective doubling times” on serial mammography range from 10 to >700 days with a median of approximately 200 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. One of our models is biologically based and includes parameters of a 200 day effective doubling time, 7% prevalence of occult tumors in the 40-80 aged female population and a detection threshold of 1.16 cm and the other involves computer based projections based on age related breast cancer incidence. Our models facilitate interpretation of the Women's Health Initiative (WHI) and anti-estrogen prevention studies. The biologically based model suggests that menopausal hormone therapy with conjugated equine estrogens plus medroxyprogesterone acetate (MPA) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. The paradoxical reduction of breast cancer incidence in women receiving estrogen alone is consistent with a model that this hormone causes apoptosis in women deprived of estrogen long term as a result of the cessation of estrogen production after the menopause. Understanding of the kinetics of occult tumors suggests that breast cancer “prevention” with anti-estrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation. Our in vivo data suggest that the combination of a SERM, bazedoxifene (BZA), with conjugated equine estrogen (CEE) acts to block maturation of the mammary gland in oophorectomized, immature mice. This hormonal combination is defined by the generic term, tissue selective estrogen complex or TSEC. Xenograft studies with the BZA/CEE combination show that it blocks the growth of occult, hormone dependent tumors in nude mice. These pre-clinical data suggest that the BZA/CEE TSEC combination may prevent the growth of occult breast tumors in women. Based on the beneficial effects of this TSEC combination on symptoms and fracture prevention in menopausal women, the combination of BZA/CEE might be used as a means both to treat menopausal symptoms and to prevent breast cancer.

Link to Article

http://dx.doi.org/10.1016/j.jsbmb.2013.05.008

Short-courses of dexamethasone abolish bisphosphonate-induced reductions in bone toughness

Authors

Tianyi D. Luo and Matthew R. Allen

Abstract

Atypical femoral fractures, which display characteristics of brittle material failure, have been associated with potent remodeling suppression drugs. Given the millions of individuals treated with this class of drugs it is likely that other factors play a role in these fractures. Some evidence suggests concomitant use of corticosteroids may contribute to the pathogenesis although data in this area is lacking. The goal of this study was to assess the combined role of bisphosphonates and dexamethasone on bone mechanical properties. Skeletally mature beagle dogs were either untreated controls, or treated with zoledronic acid (ZOL), dexamethasone (DEX), or ZOL + DEX. Zoledronic acid (0.06 mg/kg) was given monthly via IV infusion for 9 months. DEX (5 mg) was administered daily for one week during each of the last three months of the 9 month experiment. Ribs were harvested and assessed for bone geometry, mechanical properties, and remodeling rate (n=3-6 specimens per group). DEX significantly suppressed intracortical remodeling compared to vehicle controls while both ZOL and the combination of DEX+ZOL nearly abolished intracortical remodeling. ZOL treatment resulted in significantly lower bone toughness, determined from 3-point bending tests, compared to all other treatment groups while the toughness in ZOL+DEX animals was identical to those of untreated controls. These findings suggest not only that short-courses of dexamethasone do not adversely affect toughness in the setting of bisphosphonates, they actually reverse the adverse effects of its treatment. Understanding the mechanism for this tissue-level effect could lead to novels approaches for reducing the risk of atypical femoral fractures.

Link to Article

http://www.iupui.edu/~bonelab/BONE-accepted%20version.pdf

Epithelial 11β-hydroxysteroid dehydrogenase type II deletion inhibits Apc+/min mouse tumorigenesis via COX-2 pathway inhibition and induction of G1 cell cycle arrest

Authors

Li Jiang, Shilin Yang, Huiyong Yin, Xiaofeng Fan, Suwan Wang, Bing Yao, Ambra Pozzi, Xiaoping Chen, Raymond C. Harris, and Ming-Zhi Zhang

Abstract

Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) promotes colorectal tumorigenesis. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are down-regulated by 11beta-hydroxysteroid dehydrogenase type II (11ßbetaHSD2)-mediated metabolism. We previously reported that 11betaHSD2 increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity, and 11betaHSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. 11betaHSD2 is expressed in Apc+/min mouse intestinal adenoma stromal and epithelial cells. We generated Apc+/min mice with selective deletion of 11betaHSD2 in intestinal epithelial cells (Vil-HSD2-/- Apc+/min). 11betaHSD2 deletion in intestinal epithelia led to marked inhibition of Apc+/min mouse intestinal tumorigenesis. Immunostaining indicated decreased 11ßHSD2 and COX-2 expression in adenoma epithelia, while stromal COX-2 expression was intact in Vil-HSD2-/- Apc+/min mice. In Vil-HSD2-/- Apc+/min mouse intestinal adenomas, both p53 and p21 mRNA and protein levels were increased, with concomitant decrease in phosphorylation of retinoblastoma protein, indicating glucocorticoid-mediated G1 cell cycle arrest. Regulated in development and DNA damage responses 1 (REDD1), a novel stress-induced gene that inhibits mammalian target of rapamycin (mTOR) signaling pathway, was increased, while the mTOR signaling pathway was inhibited. Therefore, in Vil-HSD2-/- Apc+/min mice, epithelial cell 11betaHSD2 deficiency leads to inhibition of adenoma initiation and growth by attenuation of COX-2 expression, increased G1 cell cycle arrest and inhibition of mTOR signaling as a result of increased tumor intracellular active glucocorticoids. 11betaHSD2 inhibition may represent a novel approach for colorectal cancer chemoprevention by increasing tumor glucocorticoid activity, which in turn inhibits tumor growth by multiple pathways.

Link to Article

http://dx.doi.org/10.1158/1541-7786.MCR-13-0084-T

Age-related CXC chemokine receptor-4-deficiency impairs osteogenic differentiation potency of mouse bone marrow mesenchymal stromal stem cells

Authors

Liang G. Guang, Adele L. Boskey, Wei Zhu

Abstract

Cysteine (C)-X-C chemokine receptor-4 (CXCR4) is the primary transmembrane receptor for stromal cell-derived factor-1 (SDF-1). We previously reported in mouse or human bone marrow-derived mesenchymal stromal stem cells (BMSCs) that deleting or antagonizing CXCR4 inhibits bone morphogenetic protein-2 (BMP2)-induced osteogenic differentiation. The goal of this study was to determine whether CXCR4-deficiency in BMSCs is an age-related effect in association with impaired osteogenic differentiation potency of aged BMSCs. Using BMSCs derived from C57BL/6J wild type mice at ages ranging from 3 to 23 months old, we detected decreased CXCR4 mRNA and protein expression as well as SDF-1 secretion with advancing aging. Moreover, CXCR4-deficient BMSCs from elderly vs. young mice exhibited impaired osteogenic differentiation in response to BMP2 stimulation or when cultured in dexamethasone (Dex)-containing osteogenic medium, evidenced by decreased alkaline phosphatase activity, osteocalcin synthesis, and calcium deposition (markers for immature and mature osteoblasts). Mechanistically, impaired BMP2- or Dex-osteoinduction in BMSCs of elderly mice was mediated by inhibited phosphorylation of intracellular R-Smads and Erk1/2 or Erk1/2 and p38 proteins, and decreased Runx2 and Osx expression (osteogenesis “master” regulators) were also detected. Furthermore, adenovirus-mediated repair of CXCR4 expression in BMSCs of elderly mice restored their osteogenic differentiation potentials to both BMP2 treatment and osteogenic medium. Collectively, our results demonstrate for the first time that CXCR4 expression in mouse BMSCs declines with aging, and this CXCR4-deficiency impairs osteogenic differentiation potency of aged BMSCs. These findings provide novel insights into mechanisms underlying age-related changes in BMSC-osteogenesis, and will potentiate CXCR4 as a therapeutic target to improve BMSC-based bone repair and regeneration in broad orthopedic situations.

Link to Article

http://dx.doi.org/10.1016/j.biocel.2013.05.034

Neuropeptide Y modulates fracture healing through Y1 receptor signaling

Authors

Daniela M. Sousa, Michelle M. McDonald, Kathy Mikulec, Lauren Peacock, Herbert Herzog, Meriem Lamghari, David G. Little, Paul A. Baldock

Abstract

Neuropeptide Y acting via it's Y1 receptor represents a powerful pathway in the control of bone mass. The global or osteoblast-specific Y1 receptor deletion induces pronounced bone anabolic effects in mice. However, the contribution of Y1 receptor deletion in bone repair/healing remained to be clarified. Therefore, in this study we characterized the role of Y1 receptor deletion in fracture healing. Closed tibial fractures were generated in germline (Y1−/−) and osteoblastic-specific Y1 receptor knockout mice. The progression of tibial repair monitored from 1- until 6-weeks post-fracture demonstrated that in Y1−/− mice there is a delay in fracture repair, as seen by a decrease in bone callus volume and callus strength. Moreover, the histological features included elevated avascular and cartilage area and consequently delayed cartilage removal, and hence impaired union. Interestingly, this delay in bone repair was not related directly to Y1 receptors expressed by mature osteoblasts. These findings suggest that the global absence of the Y1 receptor delays fracture healing, through impairing the early phases of fracture repair to achieve bony union. The data acquired on the role of Y1 receptor signaling disruption in bone regeneration is critical for the design of future therapeutic strategies.

Link to Article

http://dx.doi.org/10.1002/jor.22400

Black Bears With Longer Disuse (Hibernation) Periods Have Lower Femoral Osteon Population Density and Greater Mineralization and Intracortical Porosity

Authors

Samantha J. Wojda, David R. Weyland, Sarah K. Gray, Meghan E. Mcgee-Lawrence, Thomas D. Drummer, Seth W. Donahue

Abstract

Intracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age-related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25–7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age-related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse- or age-related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age- and disuse-related osteoporoses in humans.

Link to Article

http://dx.doi.org/10.1002/ar.22720