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Posts Tagged ‘RANKL’


Role of Progesterone in Breast Cancer Progression

Author: Tilda Barliya PhD

Breast Cancer has been long discussed herein focusing on different aspects of the diseases: from diagnosis and all the way up to treatment modalities (I). The literature has put a lot of emphasis on the role of Estrogen receptor in the development of breast cancer, yet not much focus was placed on the counterpart partner–Progesterone Receptor.

Progesterone:

Progesterone is secreted by the empty egg follicle after ovulation has occurred. It is highest during the last phases of the menstrual cycle, after ovulation. Progesterone causes the endometrium to secrete special proteins to prepare it for the implantation of a fertilized egg (2). If conception has occurred, progesterone becomes the major hormone supporting pregnancy, with many important functions:

  • Responsible for the growth and maintenance of the endometrium
  • Suppresses further maturation of eggs by preventing release of LH and FSH (Follicle Stimulating Hormone).
  • By relaxing the major muscle of the uterus, progesterone prevents early contractions and birth.
  • It thicken the muscle, helping the body prepare for the hard work of labor.
  • Suppresses prolactin (the primary hormone of milk production), preventing lactation until birth

A recent review by Prof. Cathrin Brisken from ISREC- Swiss Institute for Experimental Cancer Research, summarizes and highlights the important role of progesterone in breast cancer progression (1). So where do we stand?

“The ovarian steroid hormones, 17β‑oestradiol and progesterone, are pivotal in the control of breast development and physiology, and both experimental and  epidemiological studies indicate that the two hormones are intimately linked to mammary carcinogenesis”.

“Ever since the 1960s,  pharmacological antagonists of both estrogen and progesterone were developed. PR antagonists failed in the clinic because of severe side effects, such as liver toxicity. By contrast, drugs that interfere with estrogen signalling, such as tamoxifen and aromatase inhibitors have become mainstays of breast cancer therapy; they substantially prolong survival and have saved many lives”.

Agonists for both receptors have been developed and are used for both contraception and hormone replacement therapy (HRT), but there are growing concerns that they may increase breast cancer risk. Women receiving HRT have little or no increase in breast cancer risk when taking estrogens only, in fact there may even be a protective effect (1,3).

“By contrast, a substantial increase in breast cancer risk was noticed in women taking combinations of an estrogen and various synthetic progesterone agonists (progestins). This could be related to the increase in cell proliferation in the breast epithelium that has been reported with combination therapy”. These results however differ between women who took natural progesterone and those who received the synthetic form- progestin, which may be due to the fact that progestin may bound other nuclear receptors (i.e androgen and glucocorticoid receptors). Other factors aside from progesterone may advances this higher risk for HRT-related breast cancer and include for example breast density (fatty pad density).

Cellular Mechanism:

“Across species, ERα and PR are absent from the myoepithelial cells and basal cells and are expressed by 30–50% of the luminal cells. Most cells co-express ERα and PR, which is consistent with PR being an ERα target. A small subset of cells expresses either only ERα or only PR”.  It was found that cells that are either or both hormone receptor(s) positive may affect neighboring cells in a paracrine fashion by secreting signalling and proliferating factors . Some of the attractive target genes of this hormones include but excluded to WNT, fibroblast growth factors (FGF), epidermal growth factor (EGF) as well as direct intercellular signalling mediated by Notch, ephrins or gap junctions.

Hormone Receptor (HR)+ cells seem to act as ‘sensor’ cells that translate the signals encoded by systemic hormones into local paracrine signals. To relay these signals they secrete paracrine factors that bind to receptors on HR–, luminal and basal cells, which act as the ‘secondary responder cells”.

This organizing principle ensures that the signal is amplified and prolonged in time and provides a means of coordinating different biological functions of distinct cell types.

Several experiments in MCF-7 cells showed that if a cell had recently been stimulated by estrogens it would be hormone receptor (HR)–. More so, later experiments showed that the HR expression, rather positive or negative, is a hallmark of a distinct cell type in the mammary epithelium.

There are many alternations in global gene expressions and protein factors during each menstrual cycle and more over in the life time of a woman. The entire sum of changes in the different cell population determine the proliferation and development of breast cancer.

There are two types of proliferation, cell-intrinsic and paracrine proliferation. For example, it was found in mice model, that the cell-intrinsic action of progesterone on HR+ cell proliferation requires cyclin D1. Whereas the proliferation of HR– cells does not (1).

Proliferation of HR– cells on progesterone stimulation requires RANKL, which is a tumour necrosis factor‑α (TNFα) family member. It was further noted that that RANKL is a crucial mediator of PR signalling function.

It is believed that recurrent activation of PR during repeated menstrual cycles and its downstream effectors, cyclin D1, WNT4 and RANKL promotes breast carcinogenesis (Fig.1). It was found for instance, that use of PR agonists or ectopic expression of RANKL induce mammary tumors in mice models.

Therefore, of clinical relevance  for example, soluble RANKL administered intravenously can elicit proliferation in the mammary epithelium, and systemic administration of its decoy receptor osteoprotegerin (OPG) can inhibit proliferation (1). There are obviously other genes associated with these phenotypes and the RANKL was given as an example.

Cathrin Brisken 2011

Novel preventive strategies are envisioned to PR itself and its downstream mediators. The new generation of selective progesterone receptor modulators (SPRMs)  used for gynaecological disorders, have fewer side effects than earlier ones, and are thought to be introduced as potential breast cancer therapy.

Reproductive hormones impinge on breast carcinogenesis at all stages and can determine whether the disease will progress (Fig 1). In particular, PR signalling has a pivotal role in controlling tumour promotion from the in situ stage onwards.

Clinical Aspect

Breast Cancers are generally divided into molecular subtypes which include:

  • Basal-like: ER-, PR- and HER2-; also called triple negative breast cancer (TNBC). Most BRCA1 breast cancers are basal-like TNBC.
  • Luminal A: ER+ and low grade
  • Luminal B: ER+ but often high grade
  • Luminal ER-/AR+: (overlapping with apocrine and so called molecular apocrine) – recently identified androgen responsive subtype which may respond to antihormonal treatment with bicalutamide.  
  • ERBB2/HER2+: has amplified HER2/neu.
  • Normal breast-like
  • Claudin-low: a more recently described class; often triple-negative, but distinct in that there is low expression of cell-cell junction protein including E-cadherin and frequently there is infiltration with lymphocytes.

NCCN 2007

Onitilo et al suggested this subgroups in their 7-year retrospective study(6):

  • ER/PR+, Her2+ = ER+/PR+, Her2+; ER−/PR+, Her2+; ER+/PR−, Her2+

  • ER/PR+, Her2− = ER+/PR+, Her2−; ER−/PR+, Her2−; ER+/PR−, Her2−

  • ER/PR−, Her2+ = ER−/PR−, Her2+

  • ER/PR−, Her2− = ER−/PR−, Her2−

The independent prognostic and predictive role of PR expression irrespective of ER has been a subject of great controversy.

In their study, Onitilo & colleagues have evaluated numerous patients for different factors such as five-year overall and disease-free survival, recurrent site and age, depending on their subgroups (6).

Their study supports other studies which have shown both the triple negative and Her2+/ER− subtypes to have poorer clinical, pathologic and molecular prognoses. The triple negative group has the worst overall and disease-free survival. More so the prognosis according to ER/PR status was found to be:

ER-positive/PR-positive tumors >> ER-positive/PR-negative tumors >>> ER-negative/PR-negative tumors.

But what happens with the ER-negative/PR positive group? How many patients fall into this category and how important that is? Could it be an artifact?

Maleki et al believes that in their study tumor that were initially reported as ER-negative/PR-positive are actually grade I (low grade) ER positive tumors such as infiltrating lobular carcinoma and colloidal carcinoma (7).

Summary:

Reproductive hormones impinge on breast carcinogenesis at all stages and can determine whether the disease will progress. In particular, PR signalling has a pivotal role in controlling tumour promotion from the in situ stage onwards. It will therefore be a good opportunity to design new treatment strategies that include selective progesterone receptor inhibitors. Interfering with the breast-specific effects of increased serum progesterone levels may be an effective way to reduce their risk of dying of breast cancer without blocking all reproductive function.More so, the majority of the physicians and researchers would agree that more studies are necessary to refine IHC classification for better classification and clinical use.

Reference:

1. Cathrin Brisken. Progesterone signalling in breast  cancer: a neglected hormone coming  into the limelight. Nature Reviews Cancer June 2013, (13): 385-396. http://www.nature.com/nrc/journal/v13/n6/full/nrc3518.html

2. Nicole Galan RN. What is Progesterone? http://pcos.about.com/od/normalmenstrualcycle/f/Progesterone.htm

3. Anderson, G. L. et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012. 13, 476–486.

4. MJ, Möller MF, DG, Niggemann B, Zänker KS and Entschladen F. Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism. BMC Cancer 2011, 11:158. http://www.biomedcentral.com/1471-2407/11/158

5. MCU Cheang, J Parker, K DeSchryver, J Snider, T Walsh, S Davies, A Prat, T Vickery, J Reed, B Zehnbauer, S Leung, D Voduc, T Nielsen, E Mardis, P Bernard, C Perou, and M Ellis. Luminal A vs. Basal-like Breast Cancer: time dependent changes in the risk of relapse in the absence of treatment. Cancer Research: December 15, 2012; Volume 72, Issue 24, Supplement 3. http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/72/24_MeetingAbstracts/P6-07-10

6. Onitilo AA., Engel JM., Greenlee RT and Mukesh BN. Breast Cancer Subtypes Based on ER/PR and Her2 Expression: Comparison of Clinicopathologic Features and Survival. Clinical Medicine & Research  2009 June 1 7 (1-2); 4-13. http://www.clinmedres.org/content/7/1-2/4.long

7. Maleki Z., Shariat S., Mokri M and Atri M.  ER-negative /PR-positive Breast Carcinomas or Technical Artifacts in Immunohistochemistry? Arch Iran  Med. 2012; 15(6): 366 – 369. http://www.ams.ac.ir/AIM/NEWPUB/12/15/6/0010.pdf

Other articles from our Open Access Jounal:

I By: Larry Bernstein MD. “recurrence risk for breast cancer”. https://pharmaceuticalintelligence.com/2013/03/02/recurrence-risk-for-breast-cancer/

II. By: Ritu Saxena PhD. “In focus: Triple Negative Breast Cancer”. https://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

III. By: Tilda Barliya PhD. The Molecular pathology of Breast Cancer Progression. https://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/

IV. By: Sudipta Saha PhD. The FEMALE reproductive system and the hypothalamic-pituitary-thyroid axis. https://pharmaceuticalintelligence.com/2012/12/11/the-female-reproductive-system-and-the-hypothalamic-pituitary-thyroid-axis/

V. By: Tilda Barliya PhD. Nanotech Therapy for Breast Cancer. https://pharmaceuticalintelligence.com/2012/12/09/naotech-therapy-for-breast-cancer/

 

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Targeting bone turnover by nature-derived agents for deriving effective treatment of PCa metastases

Reporter: Ritu Saxena, Ph.D.

Introduction and basis of research: Prostate Cancer (PCa) is a leading cause of cancer-related deaths in the men of United States. Metastasis development results in high mortality rate in prostate cancer patients and PCa frequently metastasizes to the bone.

Using nature-derived agents, scientists at the Wayne State University School of medicine, Detroit, Michigan targeted bone remodeling – both bone formation and bone resorption, and proposed it as an effective strategy for the treatment of PCa bone metastasis. The treatment strategy was based on the recent observations pointing towards an increase in both osteoclastic activity and osteoblastic activity in PCa bone metastases which is contrary to the earlier belief that metastases is osteoblastic. Thus, authors designed a study targeting that both osteoclasts (bone forming cells) and osteoclasts (bone resorbing cells) activity for the treatment of PCa bone metastases

Study design: Li et al utilized formulated isoflavone and 3,39-diindolylmethane (BR-DIM) for the suppression of bone remodeling in PCa bone metastases. 3,39-diindolylmethane (DIM) is a natural agent mainly found in the members of the family Cruciferae such as broccoli, and Isoflavone is mainly found in soyabean. Isoflavone genistein has been reported to have the ability to inhibit cancer cell growth both in vitro and in vivo without toxicity. BR-DIM (manufactured by BioResponse, LLC.), as stated by the authors “could downregulate the expression of AR, Akt and NF-kB, leading to the inhibition of PCa growth and the induction of apoptosis in vitro”.  Authors thus, set out to test the hypothesis that “ a mixture of isoflavone and BR-DIM could inhibit the differentiation of osteoclasts and osteoblasts mediated through regulation of cellular signaling pathways that are involved in bone remodeling and PCa bone in vivo”.

A co-culture system involving pre-osteoclastic cell line-RAW264.7 cells, pre-osteoblastic cell line hFOB1.19, and several PCa cell lines, was established to determine how the PCa cells affect differentiation of bone cells. The effect of isoflavone and BR-DIM was then tested on both osteoclast and osteoblast differentiation and PCa cells in the co-culture system.

Results: Isoflavone and BR-DIM inhibited bone remodeling through the inhibition of cell signal transduction associated with osteoclast differentiation (RANKL-mediated signaling), osteoblast differentiation (RUNX2, periostin gene), and PCa growth and signaling. Isoflavone and BR-DIM, infact, were shown to affect multiple signaling pathways that could possibly be useful in the prevention of PCa progression especially in the context of bone metastases.

The study highlights an important message that natural agents could be a source for deriving agents that could be useful in the treatment of diseases such as cancer without toxicity issues.

Sources: Research Article – Li Y, Kong D, Ahmad A, Bao B, Sarkar FH. Targeting bone remodeling by isoflavone and 3,3′-diindolylmethane in the context of prostate cancer bone metastasis. PLoS One. 2012;7(3):e33011. http://www.ncbi.nlm.nih.gov/pubmed?term=22412975

UroToday report: http://www.urotoday.com/UroToday/Prostate-Cancer/targeting-bone-remodeling-by-isoflavone-and-3-3-diindolylmethane-in-the-context-of-prostate-cancer-bone-metastasis-beyond-the-abstract-by-fazlul-h-sarkar-phd-et-al.html

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Reporter: Aviral Vatsa PhD, MBBS

A new study in JBMR highlights a novel glucocorticoid receptor modulator Compound A (CpdA) with the potential for an improved risk/benefit profile. They tested the effects of CpdA on bone in a mouse model of GC‐induced bone loss.

This study underlines the bone‐sparing potential of CpdA and suggests that by preventing increases in the RANKL/OPG ratio or DKK‐1 in osteoblast lineage cells, GC‐induced bone loss may be ameliorated. © 2012 American Society for Bone and Mineral Research.

RESULTS

PRED reduced the total and trabecular bone density in the femur by 9% and 24% and in the spine by 11% and 20%, respectively, whereas CpdA did not influence these parameters. Histomorphometry confirmed these results and further showed that the mineral apposition rate was decreased by PRED whereas the number of osteoclasts was increased. Decreased bone formation was paralleled by a decline in serum P1NP, reduced skeletal expression of osteoblast markers, and increased serum levels of the osteoblast inhibitor dickkopf‐1 (DKK‐1). In addition, serum CTX‐1 and the skeletal RANKL/OPG ratio were increased by PRED. None of these effects were observed with CpdA. Consistent with the in vivo data, CpdA did not increase the RANKL/OPG ratio in MLO‐Y4 cells. Finally, CpdA also failed to transactivate DKK‐1 expression in bone tissue, BMSCs and osteocytes.

METHODS

Bone loss was induced in FVB/N mice by implanting slow‐release pellets containing either vehicle, prednisolone (PRED) (3.5 mg), or CpdA (3.5 mg). After 4 weeks, mice were killed to examine the effects on the skeleton using quantitative computed tomography, bone histomorphometry, serum markers of bone turnover, and gene expression analysis. To assess the underlying mechanisms, in vitro studies were performed with human bone marrow stromal cells (BMSCs) and murine osteocyte‐like cells (MLO‐Y4 cells).

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