Estrogen Receptors And Cancer

When we get into the estrogen receptors and cancer, the complexity evident in hormones really increases.  

The discussion of estrogen has to begin with the estrogen receptors because the estrogen receptors are critical in determining the signal that is transmitted from the different estrogens. Estrogen receptors and cancer is a complex subject that needs to be broken down and explained so a thorough understanding can be attained.

For the men in the audience, I can hear their collective: “I could have told you that…”  But, for the women in the audience, at least it takes 2 because in men it only takes 1  hormone receptor to drive the show. The majority of the current research around estrogen receptors is in breast and prostate cancer. However, estrogen receptors are ubiquitous in the body and play a significant role in normal physiology [1].

The current understanding is that there are 2 estrogen receptors: estrogen receptor alpha (ER-alpha) and estrogen receptor beta (ER-beta).  These two different estrogen receptor types appear to have some specific tissue-specific expression [2] and can produce profoundly different results when stimulated.  As it relates to a wide variety of diseases, including cancer, ER-alpha has been shown to produce a pro-inflammatory [3] and pro-growth [4] signal from estrogen stimulation.

Inflammation is a prerequisite for cancer initiation and pro-growth signaling will favor cancer growth and progression. 

After all, cancer is synonymous with unregulated growth. The often-mentioned ER+ in some cancer types is, in fact, a reference to ER-alpha. One cannot say all ER-alpha expression is associated with cancer, but the scientific literature does point to an increased cancer risk with increased ER-alpha expression and signaling.

ER-alpha expression and stimulation has been shown to play roles in breast cancer [5] and prostate cancer [6] to name a few.  In fact, the loss of ER-beta expression and increase in ER-alpha expression has been shown to play a significant role in the initiation, growth, and invasion of prostate cancer [7], breast cancer [8], ovarian cancer and colorectal cancer [9]. Kind of important!

In contrast to ER-alpha, ER-beta has been shown to produce an anti-inflammatory [10] and anti-growth [11] signal from estrogen stimulation. ER-beta stimulation has even been shown to benefit asthma [12] and the excitotoxic diseases [13] MS, Parkinson’s disease, Alzheimer’s, and ALS. It doesn’t take a rocket scientist to see the potential positive impact on many diseases, including cancer, through ER-beta stimulated inflammation reduction and growth restriction to increase healthy and disease-free living potential.

Does ER-alpha always produce a pro-inflammatory signal?  Does ER-beta always produce an anti-growth response?  Are these receptors tissue specific?  Can the expression of ER-alpha and ER-beta change?  These are some of the questions that have yet to be answered by current science.

 Similar to genetic expression and hormone expression, estrogen receptor expression can change. Maybe this can explain some of the variations in hormone response between individuals?

Or maybe this can explain the response difference and cancer risk in women to Hormone Replacement Therapy (HRT) in the years of pre-menopause, perimenopause and those that are post-menopause. The perfect example of the changes that can occur in ER expression and their effects on cancer risk can actually be found in men.

Estrogen receptors are an equal opportunity offender and in the case of men with low testosterone, there is a shift from ER-beta dominance to ER-alpha dominance in the prostate [14]. Remember, ER-alpha produces a pro-inflammatory and a pro-growth signal. In addition, inflammation up-regulates aromatase activity which increases testosterone to estrogen production to further increase estrogen production and stimulation of ER-alpha.  What a vicious cycle!

The simple and linear thinking is that estrogen equals cancer in women and testosterone equals cancer in men. 

No linear thinking here.  The slogan is to keep it simple stupid.  The problem is that ignorance of the complex for the purpose of the simple is more than stupid, it is dangerous.  Accepting the complex as complex makes it simple.  Moving on.

 Keeping the focus on estrogen receptors in male cancer, the loss of ER-beta expression in the prostate has been shown to increase prostate cancer. In a recent study in mice, loss of ER-beta expression was found to increase abnormal prostate cell growth [15].

Another study in mice, found ER-beta stimulation lead to a decrease in prostate size and triggered programmed cell death through a process called apoptosis [16]. Apoptosis is a critical cancer control mechanism that is often lost early in cancer development.

However, we are talking about humans here. In human studies, ER-beta expression has been shown to reduce the incidence of prostate cancer [17] [18]. Looks pretty promising that ER-beta expression in the male prostate is protective against prostate cancer and prostate disease.

Dr. Nathan Goodyear Explains The Complexity of Estrogen Receptors and Cancer in This Video

Just to stir things up a little more and to show the insane yet beautiful complexity that really exists in hormone receptors, I present Estrogen-Related Receptors (ERR). Estrogen-Related Receptors exist in 3 forms: alpha, beta, and gamma [19].

These receptors are nuclear receptors just like the regular estrogen receptors. These ERR have significant similarity to estrogen receptors however, they do not respond to estrogen as do estrogen receptors [20] [21].

The exact specific substances that bind and stimulate the ERR are yet to be determined.  This is a common theme in science: the body is beautifully and wonderfully made, yet we only know a fraction of it.

The implication of estrogen receptors and cancer is that it is not the hormone levels alone that poise the sole cancer risk for the individual as it is so often misunderstood and presented. It is the combination of the type of hormone present and its interaction with the type of estrogen receptors present plays a significant part in what signal the estrogen transmits: pro-inflammatory and pro-carcinogenic or not pro-inflammatory and not pro-carcinogenic.

[1] Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. Differential neuroprotective and anti-inflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. Sep 11 2007;104(37):14813-8.

[2] Mueller SO, Korach KS. Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice. Curr Opin Pharmacol. 2001 Dec;1(6):613-9.

[3] Vegeto E, Cuzzocrea S, Crisafulli C, et al. Estrogen receptor-alpha as a drug target candidate for preventing lung inflammation. Endocrinology. 2009;151(1):174–184. doi:10.1210/en.2009-0876.

[4] Stephanie J Ellison-Zelski and Elaine T Alarid. Maximum growth and survival of estrogen receptor-alpha positive breast cancer cells requires the Sin3A transcriptional repressor. Molecular Cancer20109:263. Https://doi.org/10.1186/1476-4598-9-263.

[5] Ali S and Coombes RC. Estrogen receptor alpha in human breast cancer: occurrence and significance. J Mammary Gland Biol Neoplasia. 2000 Jul;5(3):271-81.

[6] William A. Ricke, Stephen J. McPherson, Joseph J. Bianco, Gerald R. Cunha, Yuzhuo Wang, and Gail P. Risbridger. Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling.The FASEB Journal 2008 22:5, 1512-1520.

[7] Weihua Z, Makela S, Andersson LC, et al. A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc Natl Acad Sci U S A. 2001;98(11):6330–6335. doi:10.1073/pnas.111150898.

[8] Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F. ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology. 2001;142(9):4120–4130. doi:10.1210/endo.142.9.8395.

[9] Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERb expression as a common step in estrogen-dependent tumor progression. Endocrine-Related Cancer (2004) 11 537–551.

[10] Matthew C. Catley, Mark A. Birrell, Elizabeth L. Hardaker, Jorge de Alba, Stuart Farrow, Saleem Haj-Yahia and Maria G. Belvisi. Journal of Pharmacology and Experimental Therapeutics July 2008, 326 (1) 83-88; DOI: https://doi.org/10.1124/jpet.108.136275.

[11] Zhang J, Tu Y and Smith-Schneider S. Activation of p53, inhibition of telomerase activity and induction of estrogen receptor beta are associated with the anti-growth effects of combination of ovarian hormones and retinoids in immortalized human mammary epithelial cells. Cancer Cell Int. 2005 Mar 8;5(1):6.

[12] Matthew C. Catley, Mark A. Birrell, Elizabeth L. Hardaker, Jorge de Alba, Stuart Farrow, Saleem Haj-Yahia and Maria G. Belvisi. Estrogen Receptor β: Expression Profile and Possible Anti-Inflammatory Role in Disease. Journal of Pharmacology and Experimental Therapeutics July 2008, 326 (1) 83-88; DOI: https://doi.org/10.1124/jpet.108.136275.

[13] Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007;104(37):14813–14818. doi:10.1073/pnas.0703783104.

[14] Cohen PG. Obesity in men: the hypogonadal-estrogen receptor relationship and its effect on glucose homeostasis. Med Hypotheses. 2008;70(2):358-60.

[15] Imamov O et al. Estrogen receptor beta regulates epithelial cellular differentiation in the mouse ventral prostate. Proc Natl Acad Sci U S A. 2004;101:9375-9380.

[16] Krishnana G et al. Novel ER beta selective agonists induce prostate atrophy in rodents without affecting the hypothalamo-pituitary-gonadal axis. In the Endocrine Society Annual Meeting 2004. 2004. The Endocrine Society Press. Chase, Maryland, USA. 180-181.

[17] Leav I et al. Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol. 2001;159:79-92.

[18] Horvath LG et al. Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Res. 2001;61:5331-5335.

[19] Coward P, Lee D, Hull MV, Lehmann JM. 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc Natl Acad Sci U S A. July 17 2001;98(15):8880-8884.

[20] Heard DJ, Norby PL, Holloway J, Vissing H. Human ERRgamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the audit. Mol Endocrinol. Mar 2000;14(3): 382-92.

[21] Vanacker JM. Pettersson K, Gustafsson JA, Laudet V. Transcriptional targets shared by estrogen receptor-related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ER beta. EMBO J. Aug 2 1999;18(15):4270-4279.