Growth hormone and breast cancer-Role of Growth Hormone in Breast Cancer.

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But as more of them are identified it may be possible to create tests for a combination of them that together significantly increase risk. A long-term epidemiological study showed that people with growth hormone receptor GHR deficiency do not develop Growth hormone and breast cancer Role of growth hormone in breast cancer. Although there may be future implications for hormobe cancer prevention as blood levels of IGF1 can be influenced by dietary factors, this has not been examined by this research, and requires further study. GH directly cncer the function of the lymphocytes through its receptor [ 34 ], or Queen bee diaper bag an action mediated by IGF-1 [ 35 ].

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  • Hormone therapy is used to treat cancers that use hormones to grow, such as some prostate and breast cancers.
  • Some types of breast cancer are affected by hormones, like estrogen and progesterone.
  • A hormone that helps children grow may cause breast cancer, and women with high levels are at higher risk, a new study has found.
  • There is much that we know and much that we have yet to understand.

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In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Help us improve our products. Sign up to take part. Growth hormone receptor GHR plays a vital role in breast cancer chemoresistance and metastasis but the mechanism is not fully understood. GHR was stably knocked down in ER-ve breast cancer cells and its effect on cell proliferation, metastatic behavior, and chemosensitivity to docetaxel DT was assessed.

Microarray analysis was performed to identify potential GHR downstream targets involved in chemoresistance. In contrast, activation, or overexpression of GHR increased chemoresistance and metastasis by increasing the expression and promoter activity, of ABCG2.

Further, ABCG2 knockdown significantly increased the chemosensitivity. Finally, patient-derived xenograft studies revealed the role of GHR in chemoresistance. Overall, these findings demonstrate that targeting GHR could be a novel therapeutic approach to overcome chemoresistance and associated metastasis in aggressive ER-ve breast cancers.

Breast cancer is a heterogeneous disease with diverse subtypes. The currently available therapies for metastatic breast cancer prolong patient survival for an average of only 9 months owing to the development of chemoresistance A long-term epidemiological study showed that people with growth hormone receptor GHR deficiency do not develop cancer GHR signaling is known to be involved in breast cancer development and progression 14 , 15 , GHR expression was found to be increased in breast tumors compared to the adjacent normal tissue GHR-deficient mice are less susceptible to develop neoplastic mammary lesions 18 , and GH-deficient dwarf rats are resistant to mammary carcinogenesis Experimental studies have shown that inhibition of GHR signaling leads to reduced breast cancer cell proliferation 20 , 21 , 22 , All breast tissues were obtained in compliance with the institutional guidelines under a protocol approved by the Texas Tech University Health Sciences Center El Paso Institutional Review Board, and informed consent was obtained from all patients.

The age of the patients ranged between 50 and 65 years. Also primary human breast cancer epithelial cells were isolated and enriched using a standard cell dissociation protocol 25 , Briefly, tissues were minced and digested with 0. To make the gradient we used We used passages number between 3 and 6 for the experiments. The control group was treated with vehicle. Tumor growth was monitored by weekly palpation. The tumors were surgically excised. Briefly, cells were seeded in six-well plates and allowed to adhere overnight.

After the cells were transfected, they were collected and analyzed by Western blot to confirm overexpression or silencing of gene expression. DT was administered intraperitoneally. After incubation, images were acquired using a Nikon Eclipse Ti confocal laser-scanning microscope Nikon Instruments, Inc.

Imaging was performed at various time points for different experiments. Immunohistochemical staining of human breast cancer tissue sections were performed using previously described standard protocols Briefly, specific antibodies were diluted in blocking buffer to a dilution of — Breast cancer tissue sections were deparaffinized, placed in three changes of xylene, and then hydrated in a graded alcohol series.

A colony-formation assay was performed to assess the clonogenic ability of a single cell in anchorage-independent growth conditions. Western blot analysis was performed according to standard protocols.

Briefly, whole cell lysates were prepared and total protein was extracted. Actin antibody was purchased from Sigma St. Appropriate secondary antibodies were used to probe the membranes following primary antibody incubation.

A list of primary antibodies with the respective concentrations and company catalog numbers are provided in the supplementary material document. Cell migration was assessed using the scratch assay. After the Matrigel polymerized, the Transwell chambers were placed in well plates, and 50, cells in RPMI medium containing 0. The transwell chambers were washed in water, air-dried, and imaged. These tests were performed using GraphPad Prism 5 software package version 5. GHR expression was found increased in breast cancer cell lines compared to normal epithelial cell lines.

Interestingly, we found that GHR expression directly correlated with the stage of disease progression Fig. The KM plotter is an online survival analysis tool, capable to assess the effect of 54, genes on survival using 10, cancer samples including breast, lung, ovarian, and gastric cancers. Primary purpose of the tool is a meta-analysis-based biomarker assessment. To further explore the contribution of GHR expression to breast cancer progression and its correlation with disease prognosis, we performed data mining from the publicly available Oncomine database ER negative breast cancer cell lines express higher levels of GHR.

GHR knockdown in these cells resulted in significantly reduced cell viability Fig. Furthermore, GHR silencing significantly increased apoptotic cell death Fig. We also observed increased expression of the pro-apoptotic proteins Bax, Bim, and Bak, while expression of the anti-apoptotic protein Bcl2 was reduced in GHR-silenced cells Fig.

GHR knockdown caused increased cell death compared to the control group in both cell lines. Expression levels of pro-apoptotic and anti-apoptotic proteins were determined by Western blot analyses.

Migratory capacity of GHR-silenced cells was determined using a migration assay j and k and the invasive capacity was determined by Matrigel invasion assay l and m. GHR knockdown significantly decreased the number of colonies. Results represented are mean of three independent experiments for cell viability assay, apoptosis assay, and Western blot.

Invasion, migration, and colony formation assays were repeated three times with at least six replicates. The experiments were carried out three times independently and the representative images were presented in case of Western blots, invasion, migration, and colony formation assays. This suggests that GHR plays a vital role in chemoresistance.

So, we sought to investigate the mechanism of GHR-induced chemoresistance using DT as a chemotherapeutic agent. All the experiments were repeated at least three times. Having established a link between GHR and chemoresistance, the next task was to understand the mechanism involved in GHR-induced chemoresistance.

We performed chemoresistance pathway focused PCR array to identify the differentially regulated genes. The experiments were repeated three times and the representative images were presented in case of Western blots and immunofluorescence experiments. ABCG2 promoter assay was repeated three times with five replicates. To certain extent biological actions of GH has been corroborated to its ability to induce IGF1 expression.

GHR silencing effectively reduced the viability of the cells at all time points. All the experiments were carried out three times, independently. Cell viability assay were repeated three times with at least five replicates. Next, we investigated the expression of the ABCG2. Our in vitro data suggests that GHR depletion inhibited cell viability and improved sensitivity to DT. Next, evaluating the potential effects of GHR silencing in a more clinically relevant setting using a murine xenograft transplant model is essential.

Cells were transplanted into athymic nude mice, and tumor growth was monitored by weekly palpations for 4 weeks Fig. Chemoresistance is a persistent problem in the treatment of breast cancer and is positively correlated with metastasis. The overexpression of GHR observed in primary breast cancer tissues and aggressive mouse mammary tumors suggest the involvement of GHR in breast cancer. GHR inhibition with pegvisomant a GHR antagonist induced apoptosis in breast cancer cells, which is consistent with our current findings An earlier study demonstrated that GHR expression levels are remarkably increased in metastatic breast cancer and in surrounding stromal cells compared to non-metastatic counterparts Several studies have demonstrated that invasion and migration are influenced by EMT 33 , Loss of E-cadherin expression and gain of N-cadherin expression are the primary features of EMT; these changes have been reported during breast cancer progression 35 , We speculate that the observed metastatic suppression caused by GHR silencing in the present study could be the result of altered EMT.

New approaches are required to sensitize the breast cancer cells that have either innate or acquired resistance to DT therapy. The mouse xenograft experiments showed that the primary breast cancers have high intrinsic resistance to DT treatment.

GHR knockdown in these cells reduced tumor progression and sensitized the tumors to DT. ABCG2 overexpression increased the resistance of breast cancer cells to DT, mitomycin C, doxorubicin, methotrexate, and topotecan Moreover, ABCG2 has been shown to efflux a variety of cancer drugs including anthracenes, camptothecin derivatives, methotrexate, and several tyrosine kinase inhibitors 42 , 43 , Hess, K. Estrogen receptors and distinct patterns of breast cancer relapse.

Breast Cancer Res. Mosly, D. Predictive markers of endocrine response in breast cancer. World J. Yu, F. Breast cancer prognosis signature: linking risk stratification to disease subtypes. Brief Bioinform.

These tumors are estrogen insensitive, meaning that they do not use estrogen to grow. Insulin-like growth factors and cancer. They don't cause uterine cancers and very rarely cause blood clots. Hormone therapy is also called hormonal therapy, hormone treatment, or endocrine therapy. Want an ad-free experience? Support for Caregivers. The activated receptors cause changes in the expression of specific genes, which can stimulate cell growth.

Growth hormone and breast cancer. CONTACT INFORMATION

It stops estrogen from connecting to the cancer cells and telling them to grow and divide. While tamoxifen acts like an anti-estrogen in breast cells, it acts like an estrogen in other tissues, like the uterus and the bones. Because of this, it is called a selective estrogen receptor modulator SERM. It can be used to treat women with breast cancer who have or have not gone through menopause.

Tamoxifen can be used in several ways:. Toremifene Fareston is another SERM that works in a similar way, but it is used less often and is only approved to treat metastatic breast cancer in postmenopausal women. It is not likely to work if tamoxifen has already been used and has stopped working. These drugs are pills, taken by mouth.

Some women with cancer spread to the bones may have a tumor flare with bone pain. This usually decreases quickly, but in some rare cases a woman may also develop a high calcium level in the blood that is hard to control. If this happens, the treatment may need to be stopped for a time. Depending on a woman's menopausal status, tamoxifen can have different effects on the bones. In pre-menopausal women, tamoxifen can cause some bone thinning, but in post-menopausal women it often strengthens bones to some degree.

The benefits of taking these drugs outweigh the risks for almost all women with hormone receptor-positive breast cancer. Fulvestrant is a drug that blocks and damages estrogen receptors. This drug is not a SERM — it acts like an anti-estrogen throughout the body. Fulvestrant is currently approved only for use in post-menopausal women. It is given by injections into the buttocks. For the first month, the shots are given 2 weeks apart.

After that, they are given once a month. Some hormone treatments work by lowering estrogen levels. Aromatase inhibitors AIs are drugs that stop estrogen production. Before menopause, most estrogen is made by the ovaries. AIs work by blocking aromatase from making estrogen. These drugs are useful in women who are past menopause, although they can also be used in premenopausal women in combination with ovarian suppression see below.

Use in adjuvant therapy: After surgery, hormonal therapy can be given to reduce the risk of the cancer coming back. Taking an AI, either alone or after tamoxifen, has been shown to work better than taking just tamoxifen for 5 years. For most post-menopausal women whose cancers are hormone receptor-positive, most doctors recommend taking an AI at some point during adjuvant therapy.

Right now, standard treatment is to take these drugs for aboutt 5 years, or to alternate with tamoxifen for a total of at least 5 years, or to take in sequence with tamoxifen for at least 3 years. For women at a higher risk of recurrence, an AI for 10 years may be recommended. Tamoxifen is an option for some women who cannot take an AI. This report is based on a large review that combined the results of 17 studies on the relationship between levels of insulin-like growth factor IGF1 and the development of breast cancer.

It found that women with higher levels of IGF1 were at greater risk of developing oestrogen-dependent breast cancer. The nature of the studies that were included means there is some certainty that higher hormone levels preceded the development of cancer and not vice versa.

However this is still not proof of cause and effect. Although there may be future implications for breast cancer prevention as blood levels of IGF1 can be influenced by dietary factors, this has not been examined by this research, and requires further study. Contributors from institutes in Europe, the US and Australia also took part. The study did show a positive link between the hormone and breast cancer risk, but this type of research cannot establish cause and effect.

This was a pooled analysis of raw data from 17 individual studies from 12 countries, which looked at the possible links between blood levels of insulin-like growth factor 1 IGF1 and breast cancer risk. IGF1 is a natural chemical in the body that is mainly secreted by the liver. It is essential for early growth and development. Several previous studies have indicated there may be an association, but these studies were small with inconsistent results.

It was unclear whether other factors were involved, such as menopausal status, the presence of other chemicals and the role of oestrogen. By pooling the data from several studies which were largely nested case control studies , the researchers aimed to establish the risk more precisely and to find out whether other risk factors play a role.

To identify these studies, the researchers searched one electronic database and did further searches of the reference lists of the studies they identified. It is possible they may have missed some potentially eligible studies. Differences between the individual studies also need be taken into account. For example, the population that was studied, how levels of growth hormones were measured, and the length of follow-up.

The researchers took this into account where appropriate. The researchers systematically searched a research database for studies that looked for associations between breast cancer risk, IGF1, and another chemical that binds the hormone IGF binding protein 3; IGFBP3.

The raw data from the individual studies on blood levels of IGF1 and IGFBP3 and other factors associated with breast cancer risk, such as menopausal status was collated. Established statistical techniques were used to analyse the relationship between breast cancer, IGF1 and other possible risk factors, and to calculate the risk that might be associated with increasing concentrations of IGF1. In total 17 studies matched the inclusion criteria, providing data on 4, women who developed breast cancer and 9, women who did not develop the disease and who formed the control group.

Average ages ranged from 35 to Most women had experienced pregnancy, and most menopausal women had gone through a natural menopause.

Role of Growth Hormone in Breast Cancer | Endocrinology | Oxford Academic

Transl Biomed. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: The interaction between pituitary hormones Growth Hormone-Prolactin , ovarian hormones Estradiol and growth factors forms the basis of the mechanisms underlying the growth of tumors of the breast.

Methods and Findings: We carried out this experimental research on the mitogenic role of GH and consequently on the rationale of the anticancer use of its inhibition. The levels of expression of several genes, GH and GHR, were evaluated in 39 cases of breast cancer, divided according to different risk levels on the basis of immunohistochemical and histological tests with nuclear grade. Conclusion: Research showed that breast cancers with a high and intermediate risk of recurrence are characterized by over-expression of GH and of its receptor GHR.

The expression was limited in cases with a low risk. The master regulators of breast development are the steroid hormones, estrogen and progesterone, growth hormone GH , mostly via its secretory product, insulin-like growth factor 1 IGF-1 , and prolactin [ 4 ].

Estrogen and GH are essential for breast development at puberty; prolactin stimulates the mammary glands to produce milk. Figure 1: Cooperation between direct and indirect actions of GH and prolactin on physiological pathway and tumour induction.

GH is a peptide hormone, synthesized, accumulated and secreted by the adenohypophysis. The numerous functions carried out by GH include regulation of body growth, cell proliferation and differentiation and regulation of the metabolism of proteins, lipids and carbohydrates [ 5 ]. GH also causes an increase in protein synthesis in cells with multiple mechanisms including: activation of some carriers of plasma membrane amino acids, causing increased entry into the cytoplasm, transduction of cellular mRNA even without a greater than normal concentration of amino acids, and an increase of protein synthesis by ribosomes.

Figure 3: Growth hormone interacts with many genes oncogenes and oncosuppressors that are part of growth different mechanism. At the middle of image survival, TME, angiogenesis different mechanism of growth; in red factors and enzymes that are promoted by GH to induce tumour; in green factors that are inhibited by GH. The family of cytokine receptors Class I and the family of interferon receptors Class II share structural characteristics and common signal transduction pathways with GHR.

In fact, both classes of receptor are associated with various members of the family of Janus tyrosine kinases JAK and activate a new family of transcription factors, known as transcription transducers and activators, which relate ligands to activation of gene expression [ 7 ]. To understand the actions of GH it is necessary to know the structure and expression of its receptor.

The cloning and sequencing of the GH receptor showed that this receptor exhibit considerable structural homology as well as exerting similar biological effects with prolactin receptor. A widespread distribution of variable concentrations of GHR was observed in many types of normal and tumor cells, with a marked and significant prevalence in tumor cells; this prevalence is in proportion to the proliferative index and to the invasive and metastasizing ability [ 8 ].

GHRs have been found on the cell surfaces of many tissues throughout the body; although most GHRs reside on the cell surface and in the endoplasmic reticulum, pronounced nuclear localization is noted in many cells [ 9 ].

In general, the expression of GHR can be detected with various immunohistochemical, molecular, western blot, and scintigraphy techniques, etc. The cytoplasmic synthesis of GHR has also been demonstrated at the level of the endoplasmic reticulum and the Golgi apparatus [ 10 ]. The presence of GHR in the nucleus suggests that the GH internalized in the cell can modulate the transcription of specific genes.

A direct effect of GH in the gene expression is highly probable. The GHR shares two properties of the proto-oncogenes:. In patients with complete GH deficiency, the levels of IGF-1 are always decreased, with the lowest levels found in patients with Laron dwarfism in whom the GHR is missing [ 16 ]. However, the co-localization of IGF-1 and GHR is not necessary since the role of GH in the tumor cells may be to regulate the function of the mature cells rather than to promote cell proliferation by local synthesis of IGF These two molecules do not always act in harmony; in some tissues the synthesis of IGF-1 is independent of GH [ 17 ], despite the fact that these tissues possess GHR, as shown by a powerful mitogenesis independent of IGF-1 in response to GH [ 18 ].

More in-depth studies are required to establish whether, and in what conditions and in which tissues GH can act independently of the synthesis of IGF-1 in human tumor cells. The literature contains scientific evidence relative to the mitogenic, biochemical and molecular mechanisms of action of GH and GH-correlated growth factors.

In the case of breast cancer, human recombinant GH increases tumor cell proliferation [ 1 ], increases the activity of telomerase favoring cell immortalization [ 19 - 21 ] and metastasizing of breast cancer by interruption of the cell-cell contact and increase in cell migration and invasion [ 22 ]. In addition, the GH-IGF-1 axis is over-expressed in breast cancer compared to adjacent healthy tissue [ 23 , 24 ].

There is also a considerable amount of evidence for other types of tumor, for example multiple myelomas [ 25 ] and bone tumors [ 26 , 27 ] in which GH accelerates the growth and has been found at high levels of concentration. The expression of its receptor, GHR, is found in greater concentrations in tumor cells [ 8 ]. In general, GH significantly increases the expression of the proto-oncogene cmyc [ 30 ].

We believe it is useful to repeat and stress the fact that most of the mitogenic effects of GH in somatic cells are mediated not only by hepatic IGF-1 1 but also by induction of the expression of other growth factors such as EGF [ 32 ] and VEGF-A [ 33 ], GH-correlated.

Figure 4: Prolactin has a central role in tumour onset and progression through mitogenic effect and angiogenesis also. GH directly regulates the function of the lymphocytes through its receptor [ 34 ], or with an action mediated by IGF-1 [ 35 ]. The increase of GHR in melanocytes, nevi, primary melanomas and metastatic melanomas is evidence of its activation of the tumor progression in these diseases. The expression of GHR in benign prostate hyperplasia and in carcinoma of the prostate is proportional to the aggressiveness and proliferative index of these cell clones [ 36 - 38 ].

To experimentally confirm and make clinical use of these scientific data, the non-for-profit Giuseppe Di Bella Foundation set up for medical-scientific research designed a research project for the expression of GH and GHR in breast cancer cell clones.

The study was also designed to detect the positive relationship of, and any dose-dependent relationship between concentration of GH, GHR, aggressiveness, proliferation index, resistance and metastasizing, thus ascertaining the rationality and the scientific grounds for the use of the physiological inhibitor of GH, somatostatin and analogues.

The aim of this project was to test the expression of a set of genes correlated with the pathway of GH by means of protocols of real-time quantitative PCR, starting from formalin fixed and paraffin embedded human tissues. This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. All subjects of the study gave their informed consent for anonymous data treatment according to the privacy rules.

The primers were designed using Primer 3, repeatmasker, Mfold, and PrimerBlast software. The results were analyzed by means of Data Assist v 3. The red lines indicate the FC 2 cut-off. The study described herein is a preliminary analysis, that firstly gave confirmation of the data reported in the literature regarding the systematic over-expression of GH, IGF1, and GHR, which is present not only in breast cancer, but in many even histologically different forms of cancer.

Through the differential regulation of the gene expression, autocrine GH also regulates vital molecular and biochemical mechanisms such as cell growth and survival, migration and invasion, epithelial-mesenchymal transition EMT , replication potential and oncogenic transformation. The genes that autocrine GH regulates positively or negatively to induce oncogenesis are known [ 40 ]. Our study confirmed that breast cancer with a high or intermediate risk of recurrence is generally characterized by over-expression of GH and its receptor GHR.

Since GH and correlated growth factors are over-expressed in all tumors, albeit to different extents, with activation of numerous proliferative and angiogenic signalling pathways, the negative regulation of GH by means of somatostatin has a logical explanation, and is extended to the correlated growth factors, as widely documented in the literature.

The generalized anticancer use of somatostatin can be explained since it antagonizes the common denominators and causal factors of all tumors, as well as the over-expression of the GH-GF correlated axis.

This strategy could be even reinforced by the cytostatic, differentiating, immunomodulating and trophic functions of other compounds, such as melatonin, solution of retinoids in vitamin E, vitamin D3 and vitamin C, Di Bella Method , without toxic effects, instead significantly improving quality of life, objective response and survival compared to the same tumor stages of breast cancer treated with conventional oncological protocols.

We draw attention to these concepts and these data with the intention of improving the prognosis of tumors in general and in the specific case of breast cancer, which still represents, throughout the world, the leading cause of death in women. The authors declare that there is no conflict of interest regarding the publication of this paper. All Published work is licensed under a Creative Commons Attribution 4. Visit for more related articles at Translational Biomedicine. Select your language of interest to view the total content in your interested language.

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