Free Cell Surface Receptors In Breast Cancer Cells Literature Review Example

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Abstract

Breast cancer is the form of cancer that develops in the breast tissue. It is usually represented by lump/s in the breast, dimpling and red scaly patch of the skin, change in the shape of breast, swelling in the armpit, and fluid coming from the nipple. There are different types of breast cancer, and the most important aspect of different cancers is the presence or absence of different receptors that are involved in the development or growth of cancer. Three important types of receptors that are related to breast cancer cells are Oestrogen receptor (ER) involving oestrogen, Progesterone receptor (PR) involving progesterone, and Human epidermal growth factor receptor 2 (HER2). However, there are some cells that have none of these three types of receptors. These cells are known as triple-negative, some other types of receptors such as prolactin receptor and androgen receptor are involved in this case. This paper deals with different aspects of these receptors.

Cell surface receptors in breast cancer cells

Breast Cancer
Breast cancer is the form of cancer that develops in the breast tissue. Among the most important signs of breast cancer are lump/s in the breast, dimpling and red scaly patch of the skin, change in the shape of breast, swelling in the armpit, and fluid coming from the nipple. After spread of the breast cancer, some other signs and symptoms may also appear such as swollen lymph nodes, bone pain, shortness of breath, or yellowish skin.
Figure 1: Round, smooth benign lump on a mammogram (Credit: Elk and Morrow, 2011)

Most important types of breast cancer are

“Ductal Carcinoma in Situ” (DCIS), which is considered as the most common type of non-invasive breast cancer that starts inside the milk ducts. It cannot spread to the surrounding tissues and is referred to as non-invasive.
“Invasive Lobular Carcinoma” (ILC), which is among the most common form of invasive breast cancer after IDC that develops in the milk carrying ducts and glands (lobules), and spreads in the surrounding areas.
“Invasive Ductal Carcinoma” (IDC), which is the most common form of breast cancer, and nearly 80% of all breast cancer is IDC.
“Inflammatory Breast Cancer”, which is considered as the most aggressive and rare form of cancer that begins with the swelling and reddening of the breast.

“Lobular Carcinoma in Situ” (LCIS), which can be produced in the lobules due to the abnormal growth of cells.

Cell receptors
Cell receptors are those proteins that are present inside and on the surface of cells such as breast cells in the body. These receptors also include hormone receptors. These receptors are considered as the “ears” and “eyes” of the cells as they are helpful in getting messages from different substances in the blood, and tell the cells about the line of action. In simple words, it can be said that they are involved in starting or ending a specific activity in the cell. In case, some substance attaches to the receptor in a right manner, it can result in the start of a specific activity in the cells.
Cell surface receptors in breast cancer cells
Breast cancer cells are composed of receptors that are present on the surface as well as in the cytoplasm and nucleus of the cells. These receptors are involved in the attachment of chemical messengers such as hormones resulting in changes in the cells. There are three important types of receptors that are related to the breast cancer cells:

Oestrogen receptor (ER), in which oestrogen is involved.

Progesterone receptor (PR), in which progesterone is involved.
Human epidermal growth factor receptor 2 (HER2).
Cancer cells having ERs are dependent on the oestrogen for their development, so they are also known as ER-positive (ER+) cancer cells. These types of cancer cells can be treated with the blockage of effects of oestrogen as for example with the help of drugs such as tamoxifen. Similarly, cancer cells with PR and HER2 receptors are known as PR+ and HER2+ breast cancer. In all these receptors, ERs and PRs are the most commonly found receptors on the outer surface of cells of breast cancer. Nearly, two-thirds of all types of breast cancers have these receptors on their cells. Prevalence of ER+ breast cancer has been shown in some of the countries in the figure below. On the other hand, HER2 gene is found to be mutated in about one-third of all breast cancers (Anders, Anders and Lin, 2011).
Figure 2: Prevalence of ER+ breast cancer in some of the countries (Hammond, et al., 2010)
However, there are some cells that have none of these three types of receptors. These cells are known as triple-negative, and they can express some other receptors for some other types of hormones such as prolactin receptor and androgen receptor.

ER and breast cancer

Oestrogen is a female hormone that is involved in the child-bearing stages as well as the menstrual cycle (Anders, Anders and Lin, 2011). ERs were discovered by Elwood V. Jensen in 1958 at the University of Chicago (Moore, 2012). ER+ cancers are aggravated, when these hormones come in direct contact with receptors. Oestrogen stimulates the division of cancer cells resulting in the growth of tumour.
In the development of cancer, initially the binding of oestrogen to the ER results in the proliferation of mammary cells leading to an increase in DNA replication and cell division that causes mutations. Then the oestrogen metabolism results in the production of genotoxic waste materials. These processes cause disruption of the cell cycle, DNA damage, and apoptosis, resulting in the formation of tumour.
Two forms of ER have been reported, i.e. ERα and ERβ encoded by ESR1 and ESR2 genes respectively. ERα is related to most of the breast cancers. Different forms of ESR1 gene have been found to be related to different levels of risks for developing breast cancer. However, the involvement of ERβ in breast cancer needs further investigation.
Hormone therapy for breast cancer takes place with the help of selective oestrogen receptor modulators as, for example, tamoxifen that works as ER antagonists in the breast tissue. Aromatase inhibitors can also be used for the treatment of ER+ breast cancer. However, treatment with these agents needs prior determination of breast cancer sensitivity and ER status.

PR and breast cancer

Progesterone is a steroid hormone that is produced in the ovary, and helps in the preparation and maintenance of the uterus for pregnancy. PR is a progestin-stimulated steroid receptor that belongs to the family of nuclear receptors. There are two different isoforms of PR, i.e. one is PRA and the second is PRB. PRA isoform is transcriptionally inactive and works in hormone receptor transcriptional activity. On the other hand, PRB works as transcriptional activator in most of the cells. Overall, PR has an important function in many of the reproductive events related to the establishment and regulation of pregnancy, alveolar growth and development in the breast, and sexual characteristics. PR is expressed at different levels in tissues in almost all systems of the body such as central nervous system, respiratory system, gastrointestinal system, and reproductive system. It has peak levels in the uterus and ovary, spinal cord, cerebellum, and hypothalamus. Disturbance in the functioning of PR can result in cancer such as breast cancer, ovarian cancer, and prostate cancer; metabolic disorders; and cardiovascular problems. In case of PR+ breast cancer, cells may get signals from progesterone that could result in the promotion of cancer cells.
Researchers have reported that PR status for the primary tumour has more impact on the patient survival as compared to the PR status at relapse (Lindström, et al., 2012).

HER2 and breast cancer

HER2 is also known as c-ErbB2/c-neu. It is a transmembrane glycoprotein receptor that is involved in the maintenance of cell growth, apoptosis, and survival of breast cancer cells. It is found on the surface of some types of breast cancer cells. Nearly 25% to 30% of breast cancers have an excessive amount of HER2/neu protein making the cancer more aggressive (Ahmad, 2012).
Studies have shown that nearly 1 in 4 cases of breast cancer in the U.S. is HER2+ breast cancer. HER2+ breast cancer is an aggressive form of cancer that spreads more readily and shows less response to chemotherapy and hormonal therapy. These cancers are also found to have more chances of recurrence, have poorer prognosis, and give less chances of survival as compared to the HER2-negative (HER2-) breast cancer (Ahmad, 2012).
Studies have shown that genetic mutation in the HER2 gene results in the elevated amount of the growth factor receptor protein on the surface of cancer cells. HER2 is considered to be without any ligand, so, for activation and high level of expression on the cell surface, it depends on the heterodimerization with some other HER receptors, or homodimerization with itself. Overexpression of HER2 results in the high level of HER2 dimerization; abnormal signaling as, for example, proliferation, differentiation, survival, invasion, angiogenesis, and metastasis; and eventually growth of the cancer. Usually, the development and survival signals generated by HER2 are mediated by PI3K/Akt as well as Ras/MAPK signaling pathways. Research has also shown that HER2+ breast cancer is also related to down-regulation of Signal transducer and activator of transcription (STAT) signaling pathways, which shows an important antitumor efficacy. On the other hand, HER2 induction can also result in the up-regulation of anti-apoptotic proteins survivin and Bcl-2 in the cells of breast cancer. HER2 also regulates survivin through PI3K-dependent effects on serum as well as glucocorticoid-induced kinases (SGK) and/or phospholipase γ (Ahmad, 2012).
This receptor has become one of the most important breast cancer biomarkers and targets in the present time. Moreover, targeting the HER2 signaling pathways can also help in the treatment of breast cancer patients (Ahmad, 2012).

Testing for hormone receptors

It is important to test hormone receptors as it can help in deciding the likely response of cancer to hormones. Hormone therapy can either decreases the amount of oestrogen or progesterone in the body, or it can block these hormones from helping the development and function of breast cells. On the other hand, if the breast cancer is hormone-receptor negative, i.e. cancer is developing without hormone-receptors, hormonal therapy could not work.
Immunohistochemistry (IHC) can be used to find the involvement of oestrogen in the development of cancer. IHC testing involves the detection of oestrogen and progesterone receptors in the cells of breast cancer. These cells are taken from a sample of tissue obtained from a biopsy, i.e. cutting a small amount of tissue to check under the microscope. This sample of tissue may also come from the surgery that has been done to remove all of the tumour, or some part of breast or the entire breast.
It has also been found that sometimes breast cancer cells may lose their receptors with time. On the other hand, it is also possible that hormone-receptor-negative cancers can develop or gain receptors. In cases of recurrence, doctors may prescribe to repeat the biopsy to confirm the presence of hormone receptors, and, based on the results, doctors may advice whether to continue the hormone therapy or not.
Patients may show a considerable loss and gains of ER, PR, and HER2 during the course of tumour progression Researchers have found that one-third of patients of breast cancer go through the process of changes in hormone receptor status, and nearly 15% of patients experience changes in the HER2 status during the progression of tumour. It is due to this change in receptor status, differential survival rates have been noted in women (Lindström, et al., 2012).
Researchers have reported that patients with ER+ disease after relapse of the condition show better prognosis as compared to ER- patients. ER+ patients may also show the worsening of condition as a result of HER2 status. Researchers have reported that nearly 33% of patients on hormone therapy may lose ER expression after relapse, while only 10% of untreated patients experience changed ER status. Chances of gaining ER are small in patients, who received hormone therapy, whereas in case of no treatment or chemotherapy alone, the chances are three times high (Lindström, et al., 2012).
It is obvious that the loss or decrease in ER and HER2 can result in resistance to endocrine therapy. On the other hand, gain or increase in ER and HER2 in the relapse can increase the choices of therapies helping in increasing the survival of patients (Lindström, et al., 2012).

Some recommendations for testing of cell surface receptors

In order to improve the accuracy of ER and PR testing, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have given some recommendations (Hammond, et al., 2010) such as:
In case of newly diagnosed invasive breast cancer patients or recurrence of breast cancer, presence of ER and PR has to be checked on the primary tumour and/or the surrounding areas or areas where the cancer may spread.
A tumour is considered ER+ and/or PR+ in case it has at least 1% of the cells having oestrogen and/or progesterone receptors, and in that case, patients have to talk with their doctors about the start of hormone therapy.
It is better to take larger tissue samples to test the presence of ER and/or PR. If the cancer has spread, testing of those areas is also important.
Laboratories must have accreditation with CAP or must have to fulfil the accreditation requirements to test ER and PR. These laboratories have also be inspected to confirm the guideline requirements.

Concluding Remarks

Cell surface receptors on the breast cancer have seen a high level of work in the past few decades. The identification of different roles of receptors on the surface of breast cancer cells have benefitted from molecular and genetic studies of their actions. However, in order to take the research to the next level, it is important to investigate the signalling pathways that are related to these receptors. Moreover, affect of the presence or absence of receptors on signalling pathways can also help in improving therapeutic strategies that are related to breast cancer. Another important research idea in improving therapeutic strategies is the investigation of cofactor interactions of different receptors as, for example, further investigations can be done for the interaction of progesterone receptor on androgen receptor, Krueppel-like factor 9 (KLF9), prolactin receptor, Ubiquitin-protein ligase E3A (UBE3A), and Nuclear receptor co-repressor 2. Research can also be done on the mechanisms and reasons of the spread of cancer from the breast tissues to other parts of the body, and the likely involvement of receptors in this spread of cancer.

References

Ahmad, A. 2012. Breast Cancer Metastasis and Drug Resistance: Progress and Prospects, Springer New York.
Anders, A. P. B. C. L. C. C. U. N. C. C. H. N. C. C. K., Anders, C. K. and Lin, N. U. 2011. 100 Questions & Answers About Triple Negative Breast Cancer, Jones & Bartlett Learning.
Elk, R. and Morrow, M. 2011. Breast Cancer For Dummies, Wiley.
Hammond, M. E. H., Hayes, D. F., Dowsett, M., Allred, D. C., Hagerty, K. L., Badve, S., Fitzgibbons, P. L., Francis, G., Goldstein, N. S. & Hayes, M. 2010. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Archives of pathology & laboratory medicine, 134, e48-e72.
Lindström, L. S., Karlsson, E., Wilking, U. M., Johansson, U., Hartman, J., Lidbrink, E. K., Hatschek, T., Skoog, L. & Bergh, J. 2012. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. Journal of Clinical Oncology, JCO. 2011.37. 2482.
Moore, D. D. 2012. A Conversation with Elwood Jensen. Annual Review of Physiology, 74, 1-11.