Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals

Hernández, Laura; Gregerson, Karen A.; Horseman, Nelson D.

doi:10.1152/ajpendo.00666.2011

Cited by 94 publications

(109 citation statements)

References 54 publications

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“…This suggests that physiological responses to increased serotonin concentrations are different depending on the time point that is evaluated post-treatment. We have previously shown that PTHrP reached a maximal concentration in the circulation in response to 5-HTP in mice 3 h after treatment (Hernandez et al 2012). Moreover, serotonin has been shown to cause physiological changes to tight junctions in the mammary epithelium in a biphasic manner in the mammary gland (Pai & Horseman 2008).…”

Section: Discussionmentioning

confidence: 97%

“…Serotonin is synthesized by the mammary gland in several species (Matsuda et al 2004, Hernandez et al 2009, and it regulates several aspects of mammary gland function, including milk protein gene expression, the induction of parathyroid hormone-related protein (PTHrP) production, and mammary gland Ca pumps and transport (Matsuda et al 2004, Hernandez et al 2012, Laporta et al 2013a, 2014a. The concept that the mammary gland acts as an endocrine organ that secretes PTHrP into the circulation as a signal to target tissues to regulate Ca supply to the milk during lactation is well accepted in rodents and humans (Wysolmerski 2010).…”

Section: Introductionmentioning

confidence: 99%

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Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows

Laporta

Moore

Weaver

et al. 2015

Journal of Endocrinology

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A 4!4 Latin square design in which varied doses (0, 0.5, 1.0, and 1.5 mg/kg) of 5-hydroxy-L-tryptophan (5-HTP, a serotonin precursor) were intravenously infused into late-lactation, non-pregnant Holstein dairy cows was used to determine the effects of serotonin on calcium and energy metabolism. Infusion periods lasted 4 days, with a 5-day washout between periods. Cows were infused at a constant rate for 1 h each day. Blood was collected pre-and 5, 10, 30, 60, 90, and 120 min post-infusion, urine was collected pre-and post-infusion, and milk was collected daily. All of the 5-HTP doses increased systemic serotonin as compared to the 0 mg/kg dose, and the 1.0 and 1.5 mg/kg doses increased circulating glucose and non-esterified fatty acids (NEFA) and decreased beta-hydroxybutyrate (bHBA) concentrations. Treatment of cows with either 1.0 or 1.5 mg/kg 5-HTP doses decreased urine calcium elimination, and the 1.5 mg/kg dose increased milk calcium concentrations. No differences were detected in the heart rates, respiration rates, or body temperatures of the cows; however, manure scores and defecation frequency were affected. Indeed, cows that received 5-HTP defecated more, and the consistency of their manure was softer. Treatment of late-lactation dairy cows with 5-HTP improved energy metabolism, decreased loss of calcium into urine, and increased calcium secretion into milk. Further research should target the effects of increasing serotonin during the transition period to determine any benefits for post-parturient calcium and glucose metabolism.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows

Laporta

Moore

Weaver

et al. 2015

Journal of Endocrinology

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“…Conversely, serotonin was found to stimulate tumor growth when applied to invasive breast cancer cell lines, by promoting proliferation and epithelial-mesenchymal transition (Pai et al 2009). Moreover, serotonin was found to induce the transcription of parathyroid hormone-related protein and the metastasis-associated transcription factor Runx2/Cbfal via the serotonin receptor, 5-HT2 (Hernandez et al 2012). Hence, it is plausible that the activation of the serotonin receptor pathway in tumors arising during pregnancy may play a role in controlling the aggressive clinical behavior of these tumors.…”

Section: Discussionmentioning

confidence: 99%

Biology of breast cancer during pregnancy using genomic profiling

Azim

Brohée

Peccatori

et al. 2014

Endocrine Related Cancer

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Breast cancer during pregnancy is rare and is associated with relatively poor prognosis. No information is available on its biological features at the genomic level. Using a dataset of 54 pregnant and 113 non-pregnant breast cancer patients, we evaluated the pattern of hot spot somatic mutations and did transcriptomic profiling using Sequenom and Affymetrix respectively. We performed gene set enrichment analysis to evaluate the pathways associated with diagnosis during pregnancy. We also evaluated the expression of selected cancer-related genes in pregnant and non-pregnant patients and correlated the results with changes occurring in the normal breast using a pregnant murine model. We finally investigated aberrations associated with disease-free survival (DFS). No significant differences in mutations were observed. Of the total number of patients, 18.6% of pregnant and 23% of non-pregnant patients had a PIK3CA mutation. Around 30% of tumors were basal, with no differences in the distribution of breast cancer molecular subtypes between pregnant and non-pregnant patients. Two pathways were enriched in tumors diagnosed during pregnancy: the G protein-coupled receptor pathway and the serotonin receptor pathway (FDR !0.0001). Tumors diagnosed during pregnancy had higher expression of PD1 (PDCD1; PZ0.015), PDL1 (CD274; PZ0.014), and gene sets related to SRC (PZ0.004), IGF1 (PZ0.032), and b-catenin (PZ0.019). Their expression increased almost linearly throughout gestation when evaluated on the normal breast using a pregnant mouse model underscoring the potential effect of the

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“…In human breast cancer cells, 5-HT induced both parathyroid hormone-related peptide (PTHrP) and the metastasis-associated transcription factor Runx2/Cbfa1 (22). The mammary epithelium possesses a local serotonin signaling system which drives PTHrP expression during lactation and in breast cancer cells which may be a passage of breast communication to bone through serotonergic control of PTHrP (23).…”

Section: Introductionmentioning

confidence: 99%

Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice

et al. 2015

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Abstract. Breast cancer metastasizes to the bone in a majority of patients with advanced disease resulting in bone destruction. The underlying mechanisms are complex, and both processes are controlled by an interaction between locally and systemically derived signals. Clinically, breast cancer patients with depression have a higher risk of bone metastasis, yet the etiology and mechanisms are yet to be elucidated. MDA-MB-231 breast cancer cells were used to establish a bone metastasis model by using intracardiac injection in nude mice. Chronic mild stress (CMS) was chosen as a model of depression in mice before and after inoculation of the cells. Knockdown of the RUNX-2 gene was performed by transfection of the cells with shRNA silencing vectors against human RUNX-2. A co-culture system was used to test the effect of the MDA-MB-231 cells on osteoclasts and osteoblasts. RT-PCR and western blotting were used to test gene and protein expression, respectively. We confirmed that depression induced bone metastasis by promoting osteoclast activity while inhibiting osteoblast differentiation. Free serotonin led to an increase in the expression of RUNX2 in breast cancer cells (MDA-MB-231), which directly inhibited osteoblast differentiation and stimulated osteoclast differentiation by the PTHrP/RANKL pathway, which caused bone destruction and formed osteolytic bone lesions. Additionally, the interaction between depression and breast cancer cells was interrupted by LP533401 or RUNX2 knockdown. In conclusion, depression promotes breast cancer bone metastasis partly through increasing levels of gut-derived serotonin. Activation of RUNX2 in breast cancer cells by circulating serotonin appears to dissociate coupling between osteoblasts and osteoclasts, suggesting that the suppression of gut-derived serotonin decreases the rate of breast cancer bone metastasis induced by depression. IntroductionBreast cancer is one of the most common cancers worldwide and tends to metastasize to bone, resulting in osteolysis and skeletal-related events (pain and fracture) in patients. The mechanisms underlying this metastasis are complex and involve both particular characteristics of the breast cancer cells and the bone matrix (soil and seed concept). During metastasis, breast cancer cells possess certain properties that enable them to grow in bone, and the bone matrix provides a suitable microenvironment which facilitates the growth of breast cancer cells. The bone microenvironment facilitates dynamic bone resorption and bone formation which maintains the balance of bone mass. Bone remodeling consists of both resorption by osteoclasts (1-5) and new bone formation by osteoblasts (3,5). The two processes of remodeling are coupled temporally and spatially (1,3,5,6) and are controlled by an interplay between locally and systemically derived signals, such as mechanical strain, growth factors, hormones and other molecules (1,5,6). Breast cancer cells disrupt this normal physiological process and generate factors that directly or indirectly induce th...

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Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals

Cited by 94 publications

References 54 publications

Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows

Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows

Biology of breast cancer during pregnancy using genomic profiling

Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice

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