Breast Cancer and Major Deviations of Genetic and Gender-related Structures and Function

J Clin Endocrinol Metab. 2020 Sep 1;105(9):dgaa404. doi: 10.1210/clinem/dgaa404.


We have searched the literature for information on the risk of breast cancer (BC) in relation to gender, breast development, and gonadal function in the following 8 populations: 1) females with the Turner syndrome (45, XO); 2) females and males with congenital hypogonadotropic hypogonadism and the Kallmann syndrome; 3) pure gonadal dysgenesis (PGD) in genotypic and phenotypic females and genotypic males (Swyer syndrome); 4) males with the Klinefelter syndrome (47, XXY); 5) male-to-female transgender individuals; 6) female-to-male transgender individuals; 7) genotypic males, but phenotypic females with the complete androgen insensitivity syndrome, and 8) females with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (müllerian agenesis). Based on this search, we have drawn 3 major conclusions. First, the presence of a Y chromosome protects against the development of BC, even when female-size breasts and female-level estrogens are present. Second, without menstrual cycles, BC hardly occurs with an incidence comparable to males. There is a strong correlation between the lifetime number of menstrual cycles and the risk of BC. In our populations the BC risk in genetic females not exposed to progesterone (P4) is very low and comparable to males. Third, BC has been reported only once in genetic females with MRKH syndrome who have normal breasts and ovulating ovaries with normal levels of estrogens and P4. We hypothesize that the oncogenic glycoprotein WNT family member 4 is the link between the genetic cause of MRKH and the absence of BC women with MRKH syndrome.

Keywords: WNT4; breast cancer incidence; progesterone; special populations.

Publication types

  • Review

MeSH terms

  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / etiology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms, Male / epidemiology
  • Breast Neoplasms, Male / etiology*
  • Breast Neoplasms, Male / genetics
  • Disorders of Sex Development* / complications
  • Disorders of Sex Development* / epidemiology
  • Disorders of Sex Development* / genetics
  • Female
  • Genetic Association Studies
  • Gonadal Dysgenesis / complications
  • Gonadal Dysgenesis / epidemiology
  • Gonadal Dysgenesis / genetics
  • Gonadal Dysgenesis, 46,XY / epidemiology
  • Gonadal Dysgenesis, 46,XY / genetics
  • Humans
  • Hypogonadism / complications
  • Hypogonadism / congenital
  • Hypogonadism / epidemiology
  • Hypogonadism / genetics
  • Kallmann Syndrome / complications
  • Kallmann Syndrome / epidemiology
  • Kallmann Syndrome / genetics
  • Male
  • Risk Factors
  • Transsexualism / complications
  • Transsexualism / epidemiology
  • Transsexualism / genetics
  • Turner Syndrome / complications
  • Turner Syndrome / epidemiology
  • Turner Syndrome / genetics