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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 293-296

The role of estrogen in breast cancer


1 Department of Microbiology, College of Medicine, University of Karbala, Iraq
2 AI-Ammam Al-Hussein Medical City Hospital in Karbala, Iraq

Date of Submission19-Apr-2020
Date of Acceptance02-May-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Ali Abdul Hussein S. AL-Janabi
Department of Microbiology, College of Medicine, University of Karbala, Karbala
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_59_20

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  Abstract 


Estrogen has a significant effect on the development of breast cancer. Its activities in the human body are mainly performed by binding to cellular estrogen receptor (ER). Breast cancer in relate to the presence of ER can be divided into ER-positive and ER-negative breast cancer. The role of estrogen and its receptors in the development of breast cancer will be discussed in this review.

Keywords: Breast cancer, estradiol, estrogen, estrogen receptor


How to cite this article:
Khadem R, Mahdi FC, AI-Mosawi K, S. AL-Janabi AA. The role of estrogen in breast cancer. Biomed Biotechnol Res J 2020;4:293-6

How to cite this URL:
Khadem R, Mahdi FC, AI-Mosawi K, S. AL-Janabi AA. The role of estrogen in breast cancer. Biomed Biotechnol Res J [serial online] 2020 [cited 2021 May 17];4:293-6. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/293/305645




  Introduction Top


Breast cancer is annually registered as the most common type of cancers in women with a high prevalence and incidence rate.[1],[2] It is also responsible for the high rate of mortality among females.[3] Estrogen as one of the human sex hormones[4] has been proved by many studies to be a risk factor for the development of breast cancer, especially in postmenopausal women.[5],[6],[7],[8] The main function of estrogen in the human body is regulating the work of different parts of the reproductive system.[9],[10] Its normal levels are usually higher in female than that of men.[4] The presence of cellular estrogen receptors (ERs) is the key to the physiological action of estrogen.[11],[12] Based on the presence or absence of ER, breast cancer is divided into ER positive and ER negative.[13] ER-positive breast cancer is more common than the ER-negative type.[13],[14]


  Breast Cancer Top


Any malignant disease which is simply called cancer takes the name of the organ in which it is developed in the human body. Thus, breast cancer is a type of malignant disease originating in breast tissues through the transformation of some of them into a malignant form.[15] This transformation may result from the effect of genetic and/or environmental factors and is more likely from the genetic effect after the initiation of mutation in essential genes.[16] Breast cancers can develop in both of females and males with the majority in females.[17] Several factors are associated with the development of breast cancer, including age as cancer risk increase with age without obviating the possibility of it developing at younger age,[18],[19] personal health history as with those who suffer from noninvasive ductal carcinoma,[20],[21] family history, lack of physical activity, obesity, alcohol consumption, and exposure to radiation.[15],[22],[23] Microflora of the human body can also have a role in some cases of breast cancer through their indirect effects on the causative risk factors.[24]

Breast cancer is considered the most common type of cancers among females, especially in the Western world with 1/10 lifetime risk.[1] Approximately one woman from ten is at risk of breast cancer at some point in her life.[2] New cases of breast cancer are dramatically increasing worldwide. It also the second-most common type of cancer responsible for death after lung cancer.[3] In the USA, more than 250,000 new cases were registered in 2017.[25] This number will expect to rise to 276,480 new cases in women and about 2620 cases in men in 2020.[26] Metastatic stage of breast cancer was diagnosed in 154,794 women in the United States in 2017.[27] However, the studies showed that more than 90% of breast cancer is not at metastatic stage at the time of diagnosis.[25] Breast cancer ranked first in the incidence among the females of the Eastern Mediterranean region, and also when males are included and ranked first among the cancer types in Iraq from top five cancers recorded by the WHO in 2009.[28] In Karbala which is an Iraqi province, it also registered as the first ranking type of cancer among females during 8 years (2008–2015).[29] However, Iraqi females of the middle age are the most common age group with breast cancer as concluded from the comparative study of advanced stages of breast cancer comparing 635 Iraqi females and 1305 British females.[30] From 14.3% of females with palpable breast lumps, one third has breast cancer at age 40–49 years.[31] This high rate was also recorded in Karbala province through 8 years surveillance (2008–2015) when the age-specific rate of females with breast cancer was higher at age 40–49 years.[29] From 1172 Iraqi females with breast cancer, the frequency of cancer was higher among unmarried females at younger ages (<50 years) and about 40.5% in advanced stages (III and IV Stages).[2]

Breast cancer can be classified based on histopathological criteria into ductal carcinoma of the milk duct as the most common type, and lobular carcinoma which develops in the lobules and is less common.[15] This classification has recently become less clinically utilized and replaced by a more recent classification that is based on the immunohistochemical characterization for the assessment of hormone receptor status, human epidermal growth factor receptor 2 gene over-expression or amplification and the proliferative fraction.[32] Breast cancer can also progress further to a metastatic disease, where axillary nodes are the most common sites, but distant metastases can also occur in bone and bone marrow as the major locations.[1]

Breast cancer is usually diagnosed based on the histopathological characterization.[33] Molecular methods are widely used nowadays for the diagnosis of breast cancer, because most breast cancer can develop as an effect of alteration in the DNA molecular content by mutation during the lifetime of an individual.[34] Waks and Winer divided breast cancer into three molecular categories depending on the presence or absence either of estrogen and progesterone receptors, human epidermal growth factor and triple-negative (in the absence of all three molecular markers). The three categories comprise hormone receptor-positive/ERBB2 negative (70% of patients), ERBB2 positive (15%-20%), and triple negative (15%).[25]


  Estrogen Top


Estrogen is a sex hormone in the human body that can found at high level in females and at lower level in males.[4] It mainly secreted by the ovary and placenta in female and under the direct effect of follicle-stimulating hormone and low level of luteinizing hormone from the adrenal cortex in men.[35],[36] Estrogen plays many physiological functions in the human body. Its main functions in the female include the regulation of the reproductive system and secondary sex characteristics as with breast development.[9] It also plays a role in reproductive biology and sexual behavior of males.[10]

There are three main types of estrogen that naturally produced in the human body, including estrone (E1), 17 β-estradiol (E2), and estriol (E3).[35],[36] Seventeen β-estradiol is the most active type of estrogen with several effective roles in many physiological functions ranging from regulating the activity of reproductive organs to regulating the work of other organs such as cardiovascular, immune, musculoskeletal, and central nervous system.[11]


  Estrogen Receptors Top


Estrogen can perform its activities through the attachment with specific cellular receptors called ERs, which are related to the large superfamily of nuclear receptors working as ligand-activated transcription factors.[11],[12] Passive diffusion of estrogen through cell and nuclear membrane allows contact with the ER for binding. Complex produced by estrogen ligand binding with receptors will trigger specific sequences in genes responsive to estrogen, which is called estrogen-response elements, work to regulate growth and differentiation of cells.[5],[6] The ER members have mostly similar protein structure which reflects on their performing the same functions.[11] Two conserved regions are recognized in the ER, one called domain C located in the middle of the protein, which binds with DNA, and another called domain E/F in the carboxy-terminal region, which binds with hormones.[12] ER can be found in two types, ERα and ERβ, which are encoded by two distinct genes that can be expressed in the same or different tissues.[11],[37] ERα is the main type with variable regulation of reproduction and physiological activities in the human body,[34] whereas ERβ acts as modulator to the biological activities of ERα.[37] Both ERα and ERβ have 96% identical amino acids in DNA-binding domains, whereas they have only 53% identical amino acids in their ligand-binding domain.[6]


  Estrogen and Breast Cancer Top


A specific connection between estrogen and breast cancer has been studied for more than 100 years.[5] The presence of high blood level of estrogen in patients with breast cancer is mostly demonstrated by many studies which also proved that estrogen can act as a risk factor for development of breast cancer, especially in postmenopausal women.[5],[6],[7],[8] Estradiol (E2) is the most active type of estrogen through its association with breast cancer development.[37] Clemons and Gross found evidence supporting the hypothesis that estrogen and its metabolites are associated with the initiation and promotion of breast cancer in a complex manner.[5] Catechol estrogen quinone 4 and catechol estrogen-3,4-quinones are estrogen metabolites in the human body that have a role in the initiation of breast cancer through reacting with DNA to induce oncogenic mutation.[7]

The main mechanism of estrogen in causing breast cancer usually begins from the point of estrogen metabolism that releases many estrogen metabolites which trigger a series of genotoxic and mutagenic activities, resulting to the stimulation of tissue growth.[6] These events work with the help of ER, especially ERα, in which its binding to estrogen activates oncogenic growth pathways in breast cancer cells.[34] Thus, genotoxic metabolites of estrogen, as with estradiol, can work together with ERs in the development of breast cancer.[6],[7] However, Yue et al. proposed two hypotheses to support the role of estrogen in the development of breast cancer.[7] The first hypothesis was that estrogen increases cell proliferation through the stimulation of transcription rate mediated by ER, which may increase the rate of genetic errors during DNA replication and finally to elevate the probability of cancer development in breast tissue. The second hypotheses demonstrated that quinone-derivative metabolites of estradiol can react with DNA, leading to the removal of some genetic bases by a depurination process and increasing the mutation rate during repairs of such errors.

In addition to the high level of estrogen, many endocrine-associated factors can be considered risk factors for the development of breast cancer, including high levels of androstenedione and testosterone hormones, conversion of androgens to the estrogens (estrone and estradiol), and elevated urinary levels of estrogens and androgens.[6] Women with greater urinary excretion of estrogen and androgen hormones are considered at risk to have breast cancer.[8] Postmenopausal women are considered a group prone to develop breast cancer as a result of having higher levels of estradiol.[38],[39],[40] Thus, the measurement of sex hormones in postmenopausal women can be used as a predictive marker for the diagnosis of breast cancer for up to 16–20 years.[40] Moreover, the concentration of estradiol and estrone is found higher in young women and in those with obesity, smoking (15 cigarettes per day), and alcoholic (20 g alcohol per day).[39]

Depending on the type of ER, breast cancer since 1970 has been divided into two types, ER positive and ER negative.[13] The absence of ER in ER-negative type may result from the suppression of the ER gene that initiates the DNA methylation in CpG island of the ER gene 5' region.[41] However, ER-negative breast cancer is a very active malignant type through its ability to increase the expression of the receptors of p53, cerbB2, and other epidermal growth factors than does ER-positive breast cancer.[42]

A patient with breast cancer is usually shown a variable content of ER. ER positive is mostly found at a high level among patients with breast cancer compared to those with ER negative.[13],[14] Of 234 patients with breast cancer in California, ER positive was found in 208 of them, whereas only 26 had ER negative.[14] This high rate of ER-positive breast cancer in California has been found to have no variable different in the histological type or geographical distribution.[43] ER positive is more often diagnosed as the major type in postmenopausal women with breast cancer (72%) than in premenopausal patients (57%) and the development of this type of ER in postmenopausal women was found to be increased after the treatment with some kinds of estrogen therapy.[44] Otherwise, ER type in combination with progesterone was found positive form in 66.6% of patients with breast cancer, especially in postmenopausal women, whereas negative form was found in 25.2%.[45]

The availability of many factors can be associated with increased the risk for the development of ER-positive breast cancer, such as nulliparity, delayed childbearing, early menarche, and postmenopausal obesity.[46] In the presence of primary ER-negative breast cancer, the risk for the development of contralateral breast cancer can raised compared with those with ER-positive type.[47] Race and age also effects on the presence of ER type when white postmenopausal women at age 75–79 years were shown to be more ER positive than in black premenopausal women at the age of 50 years.[48] On the other hand, Stanford and Greenberg recorded that women with white skin color were more ER positive than black women at the age of 35–54 years and the rate of ER negative can increase with age up to 50–54 years.[49]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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