Progesterone Antisense Oligonucleotides Inhibits Breast Cancer Growth

 

Hormone status of breast cancer

Breast cancer arises from the growth of an abnormal mass of cells across the breast tissues. When this tumor is examined, it may be sensitive to some female hormones like estrogen and progesterone. The cells in breast tumors have receptors for these hormones that specifically attract the hormone and circulate throughout the body helping the tumor to metastasize (Pourzand et al., 2011). Based on the status of hormones breast cancers can be divided into the following types.

 

Progesterone Receptor (PR) positive

When the breast cancer cells are sensitive to the progesterone hormone and by binding of this hormone to receptors on these cells, the growth of the tumor occurs. These tumors are classified as PR-positive. Endocrine therapy can be given to patients with PR-positive breast cancer for treatment.

 

Estrogen Receptor (ER) Positive

When the breast tumor cells have receptors specific for estrogen hormone, and binding of estrogen to these receptors helps the tumor to grow and metastasize, then these breast cancers are called ER-positive. The use of anti-estrogen therapy can be effective for the cure of patients having ER-positive breast cancer type.

 

Hormone Receptor (HR) negative

When the breast tumor cells don’t have any type of receptors specific for female hormones either estrogen or progesterone, then they are classified as HR negative. In this case, endocrine therapy is not effective.

Progesterone Receptor (PR)

PR is encoded by the PGR gene in humans. This gene is present on chromosome 11. PR is also termed NR3C3. This receptor is activated when a hormone called progesterone binds to it.

When progesterone binds to the PR, it is activated and enters the nucleus. Where it binds DNA and activates the transcription and translation of many proteins that are important components of many biological processes in the cells (Pourzand et al., 2011).

 

Progesterone Receptor (PR) mediated growth

Experimental findings have proved that Progesterone receptors PR and Epithelial growth factor EGF signaling have a deep link in accordance with the growth of breast tumors.

EGF causes the phosphorylation of Ser-294 in PR and activates it. It was found that when PR was induced in the cells the growth rate increased. Moreover, similar outcomes were seen when EGF was given. Then both PR and EGF were given to the breast cancer cell lines, and it was seen that the tumor growth increased exponentially. This shows that the serine residue in PR acts as a sensor that senses the growth factors and makes them functional in breast cancer cells. Moreover, this needs EFGR which will phosphorylate it. So, if EGF signaling is highly stimulated in the breast tissues, then PR will also be stimulated and ultimately tumor growth and progression occurs in the breast tissues.

It was observed in experiments on breast cancer cell lines that the translocation of PR into the nucleus is mediated by epithelial growth factor. This PR acts on those genes in the nucleus whose activation depends on the Ser-294 residue of the progesterone receptor. These are mostly growth factors. When the transcription and translation of these genes take place, these growth factors will increase the progression of breast cancer (Knutson & Lange, 2014).

Progestin Regulates Cellular Proliferation

The proliferation of cells depends on many signals that can be internal from within the cell or from the extracellular environments, that affect hormones and growth factors in the cell. These hormones and growth factors actually regulate the proliferation of normal and cancer cells. These are mostly upregulated in the case of cancer cells. Recently, many novel growth factors have been found within the cell that are playing a crucial role in cellular proliferation. The molecular mechanisms of these growth factors in the cells are also studied in detail.

It is found in the literature that most of the hormones that are regulating cell proliferation and growth are steroids in nature. They have a strong association with the growth-regulating signaling pathways in the cells. Progesterone is a steroid hormone that regulates the differentiation and proliferation of cells in the uterus and mammary glands. The effects of progestin on the body are cell and tissue specific. They usually affect the cells at the G1 stage of the cell cycle. The cyclin-dependent kinases CDKs at the G1 checkpoints are mediated by progestins (Lm et al., 2016).

In the breast tumor cell culture, when progestin was given, it was observed that it stimulated the proliferation of breast cancer cells simultaneously. But when progestin was given for a long time to this cell culture, it inhibited the proliferation of these cells by inhibiting G1 phase-specific cells from proliferating. Thus, the use of progestin for breast cancer patients can be an effective therapy.

Progestins decrease the activity of CDKs in the cell cycle and do not allow the cancer cells in breast tissues to divide anymore. This will ultimately stop the progression of breast tumors in patients.

In vivo research

The female breast cancer patients were given progestins randomly during a clinical trial. It was seen that the progression of the tumor was reduced in these patients by 14 to 31% as compared to those patients who were not given this therapy. findings have shown different mechanisms of action of progestins in breast cancer patients.

Progestins can interfere with the estrogen receptors ER in the cytoplasm and do not allow estrogen to bind to them. This was observed in the case of metastatic breast cancer patients that showed positive outcomes later on. Patients may have either estrogen or progesterone receptors on the walls of tumor cells. While some patients have both types of receptors on their tumor cells. Experiments showed that the reduction in the progression of breast cancer was observed more in those patients having both types of receptors as compared to the patients having a single kind of receptor on their tumor cell walls (Carnevale et al., 2007).

When tumor cells have both estrogen and progesterone receptors, their response rate to progestins was observed to be 61%. While the breast tumor cells having either estrogen or progesterone receptors showed a response rate of 20 to 30%.

 

Antisense Oligonucleotide Therapy (AOT)

It is one of the novel treatments for cancerous disorders. It is based on key and lock examples. AOT acts as a key that binds the specific lock in the cancer cells to inhibit important basic survival activities.

The Oligonucleotides are complementary to the specific sequences that are targeted to cure cancer. When these oligonucleotides bind to that specific sequence, they will inhibit the replication and survival of tumor cells. They usually block the transcription and translation processes by binding specific mRNA sequences.

 

Antisense Oligonucleotides (ASOs) targeting Progesterone Receptors in Breast Cancer

In vivo experiments were performed on mice to check the effects of antisense oligonucleotides that were designed against progesterone receptors in breast cancer cells. As mentioned earlier in this article, PR plays a very important role in stimulating the proliferation of breast cancer cells (Sixou, 2003).

When antisense oligonucleotides were given to the mice every 12 to 24 hours, they bind the progesterone receptor mRNA and stop the synthesis of PRs in the cells. It was observed that tumor growth was significantly reduced in these mice after antisense oligonucleotide therapy. Apoptosis was also seen to be increased in these tumor cells and complete tumor regression was observed in mice (Lamb et al., 2005).

This therapy is in clinical trials and hopefully will be one of the most effective therapies against breast cancer in the near future.

 

References

Carnevale, R. P., Proietti, C. J., Salatino, M., Urtreger, A., Peluffo, G., Edwards, D. P., Boonyaratanakornkit, V., Charreau, E. H., De Kier Joffé, E. B., Schillaci, R., & Elizalde, P. V. (2007). Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways. Molecular Endocrinology, 21(6), 1335–1358. https://doi.org/10.1210/me.2006-0304

Knutson, T. P., & Lange, C. A. (2014). Tracking progesterone receptor-mediated actions in breast cancer. Pharmacology and Therapeutics, 142(1), 114–125. https://doi.org/10.1016/j.pharmthera.2013.11.010

Lamb, C. A., Helguero, L. A., Giulianelli, S., Soldati, R., Vanzulli, S. I., Molinolo, A., & Lanari, C. (2005). Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice. Breast Cancer Research, 7(6). https://doi.org/10.1186/bcr1345

Lm, L., Ramesh, S., Chen, M., Edelman, A., Otterness, C., Trussell, J., & Fm, H. (2016). Progestin-only contraceptives : e ects on weight ( Review ). https://doi.org/10.1002/14651858.CD008815.pub4.www.cochranelibrary.com

Pourzand, A., Fakhree, M. B. A., Hashemzadeh, S., Halimi, M., & Daryani, A. (2011). Hormone receptor status in breast cancer and its relation to age and other prognostic factors. Breast Cancer: Basic and Clinical Research, 5(1), 87–92. https://doi.org/10.4137/BCBCR.S7199

Sixou, M. (2003). Diagnostic testing as a supportive measure of treatment strategy. Oral Diseases, 9(SUPPL. 1), 54–62. https://doi.org/10.1034/j.1601-0825.9.s1.10.x