The Possible Role of a Second X Chromosome in Breast Cancer Risk
By Aly | First published April 25, 2020 | Last modified March 1, 2023
This is a short supplement article to the section in the main article on breast cancer risk with hormone therapy in transfeminine people that can be found here.
The sex chromosomes include the X chromosome and the Y chromosome. Under normal biological circumstances, cisgender women have two X chromosomes (46,XX karyotype) while cisgender men (and transfeminine people) have one X chromosome and one Y chromosome (46,XY karyotype). The sex chromosomes determine whether the gonads will differentiate into ovaries or testes, and hence mediate a large portion of physical sexual dimorphism. However, the sex chromosomes also have effects in terms of sexual dimorphism that are independent of gonadal differentiation. Although hormone therapy appears to increase the risk of breast cancer in transfeminine people, so far breast cancer risk in transfeminine people seems to be much lower than that in cisgender women. There are a variety of possible reasons for this, as touched on elsewhere. One reason may be our lack of a second X chromosome—there is indication that our absence of a second X chromosome may be partially protective against breast cancer.
X Chromosome Abnormalities and Breast Cancer
The incidence of abnormal numbers of X chromosomes in cells (e.g., 45,X or 47,XXX karyotype) increases naturally with age (Barrios et al., 1991; Jacobs et al., 2013). X-chromosome gain is associated with more aggressive and poorly prognostic female breast cancer (Nakopoulou et al., 2007). Aberrant patterns of X-chromosome inactivation have been observed in female breast cancer cell lines and tissue specimens and are associated with worse survival rates (Lin et al., 2015; Chaligné et al., 2015). High incidence of X-chromosome gain has been observed in male breast cancer but not in control gynecomastic breast tissue (Di Oto et al., 2015; Di Oto et al., 2018). Additional findings and readings on X-chromosome abnormalities in breast cancer also exist (e.g., Spatz, Borg, & Feunteun, 2004; Sirchia, Tabano, & Miozzo, 2007; Chaligné & Heard, 2014; Richardson et al., 2006; Dawson, 1998).
X Chromosomes and Breast Cancer Risk in Chromosomal Disorders and Intersexuality
A variety of genetic disorders involving abnormal sex-chromosome configurations and/or intersexuality also provide insight on the possible involvement of X chromosomes in breast cancer risk. These conditions include Klinefelter’s syndrome (47,XXY male), complete androgen insensitivity syndrome (46,XY female), Turner syndrome (45,X or mixed 45,X/46,XX female), XX male syndrome (46,XX male), and X trisomy and tetrasomy (47,XXX and 48,XXXX female).
Klinefelter’s Syndrome (47,XXY)
Men with Klinefelter’s syndrome have a 47,XXY karyotype and hence an extra X chromosome. Because of their Y chromosome, men with Klinfelter’s syndrome have testes and develop normally as males. However, they have relatively low testosterone levels (about 260 ng/dL lower than usual), slightly increased estradiol levels (about 6 pg/mL more than normal), an increased ratio of estradiol to testosterone, and negligible progesterone (Wiki). In addition, men with Klinefelter’s syndrome show undermasculinization and sometimes have mild gynecomastia. The risk of breast cancer in men with Klinefelter’s syndrome is strongly increased relative to 46,XY men (Brinton, 2011; Sokol, 2012). The risk is estimated to be 20- to 60-fold higher in men with Klinefelter’s syndrome compared to 46,XY men and only 70% lower than the risk in 46,XX women (Brinton, 2011; Sokol, 2012; Swerdlow et al., 2005). The lifetime risk of breast cancer in men with Klinefelter’s syndrome is 4 to 8% (Sokol, 2012). Breast cancer risk in men with Klinefelter’s syndrome is much higher than that in almost any other known clinical situation in men. The typical age of diagnosis of breast cancer in men with Klinefelter’s syndrome is 58 years (Ferzoco & Ruddy, 2016). It is estimated that 7% of all men with breast cancer have Klinefelter’s syndrome (Ferzoco & Ruddy, 2016). Klinefelter’s syndrome suggests that breast cancer may be dependent on an extra X chromosome (Spatz, Borg, & Feunteun, 2004; Sacchi, 1993; Dawson, 1998), although disordered hormone levels may also be involved.
Complete Androgen Insensitivity Syndrome (46,XY)
Women with complete androgen insensitivity syndrome (CAIS) are individuals with a 46,XY karyotype and intra-abdominal testes who have a defective androgen receptor and hence are insensitive to the effects of androgens like testosterone. Due to their androgen insensitivity, CAIS women develop physically and behaviorally as females instead of as males. CAIS women naturally have male-range levels of sex hormones, including of testosterone, estradiol, and progesterone (Wiki). Relative to 46,XX women, testosterone levels are very high, estradiol levels relatively low (~35 pg/mL), and progesterone levels negligible. During adolescence, CAIS women undergo female puberty due to aromatization of testosterone into estradiol, and this results in feminization and excellent breast development, with breasts that are said to be somewhat above-average compared to those of 46,XX women.
After puberty, all clinically diagnosed CAIS women undergo gonadectomy due to a high risk of testicular cancer that’s associated with their intra-abdominal testes. Following gonadectomy, CAIS women receive estrogen replacement therapy, oftentimes if not usually only at menopausal doses. A progestogen is not usually included since CAIS women don’t have uteruses and hence don’t require the endometrial protection afforded by progestogens. Despite a 1 in 20,000 incidence of CAIS in 46,XY individuals and hence the estimated existence of hundreds of thousands of CAIS women throughout the world, breast cancer has never been reported in a CAIS woman (Hughes et al., 2012; Tiefenbacher & Daxenbichler, 2008; Hughes, 2009). It’s unlikely that breast cancer doesn’t occur in women with CAIS, but rather it’s probable that it’s rare. It’s unknown why this is the case, but major possible reasons include the relatively low estrogen exposure, lack of progesterone, and the lack of a second X chromosome. Their androgen insensitivity is unlikely to be involved as androgens, via activation of the androgen receptor, are thought to be protective in terms of breast cancer risk (Dimitrakakis, 2011). CAIS women are fascinating because they suggest that considerable breast cancer incidence isn’t an inevitable companion of normal breast development.
Turner Syndrome (45,X or Mixed 45,X/46,XX)
Women with Turner syndrome have either a 45,X karyotype or a mosaic of 45,X and 46,XX karyotypes. They often though not always have gonadal failure and hence many of them fail to undergo puberty. Gonadal failure is much more prevalent in those with a 45,X karyotype than in mosaics. When gonadal failure occurs, hormone therapy is required. Women with Turner’s syndrome have uteruses, so those who have pubertal failure receive hormone replacement with both an estrogen and a progestogen. As with CAIS women, this is often with only menopausal replacement doses. The risk of breast cancer appears to be lower in women with Turner syndrome than in regular 46,XX women (Schoemaker et al., 2008; Bösze, Tóth, & Török, 2006; Viuff et al., 2020). For example, in one large cohort study of 3,425 women with Turner syndrome and an average of 17 years of follow up, the risk of breast cancer was significantly lower than in regular 46,XX women. Interestingly, the standardized incidence ratios were 0.2 (0.0–0.9) in those with a 45,X karyotype and 0.9 (0.3–2.0) in those with 45,X and 46,XX mosaicism. In other words, those with mosaicism had a risk of breast cancer similar to that of regular 46,XX women, whereas those with a 45,X chromosome had a significantly lower risk (Gravholt, 2008).
XX Male Syndrome (46,XX)
XX males have a 46,XX karyotype. In about 90% of cases, the condition is caused by translocation of the SRY gene, which encodes the protein testis-determining factor (TDF), onto an X chromosome. As a result of this, XX males develop testes instead of ovaries, in turn developing as males instead of as females. Three case reports of breast cancer in 46,XX males exist (Berglund et al., 2017). On the basis of these cases and the small total number of cases of XX male syndrome that have been reported, it has been said that XX males are at increased risk for breast cancer analogously to men with Klinefelter’s syndrome (Spatz, Borg, & Feunteun, 2004; Giammarini, 1980).
X Trisomy (47,XXX) and Tetrasomy (48,XXXX)
So far there is no evidence of increased breast cancer risk in 47,XXX (X trisomy) or 48,XXXX (X tetrasomy) females (Spatz, Borg, & Feunteun, 2004), although most cases of these syndromes go undetected and the conditions are understudied (Goldschmidt et al., 2010; Wiki). Additional X chromosomes are inactivated in these individuals, limiting—although not fully eliminating—phenotypical abnormalities, possibly including greater breast cancer risk.
Taken together, these findings from chromosomal disorders and intersex conditions suggest that having at least two X chromosomes may greatly increase the risk of breast cancer. In addition, CAIS women suggest that normal breast development with very low breast cancer risk is possible, provided of course that the person has only one X chromosome.
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