Breast cancer represents one of the most prevalent female cancers and results in significant morbidity and mortality. Over 310,000 new cases are estimated to occur in the United States alone in 2024, resulting in 42,000 deaths (Siegel, Giaquinto, & Jemal, 2024). The risk factors for breast cancer development include genetic predisposition and epidemiologic associations related to reproductive history. Genes that, if mutated, predispose to breast cancer development have been identified. The most prominent are BRCA1 and BRCA2, which predispose to the hereditary breast and ovarian cancer syndrome and underlie about 5 % to 10 % of breast cancer cases (Yoshida, 2021). BRCA1 mutations confer a lifetime risk of breast cancer between 50 % and 85 % and of ovarian cancer between 30 % and 60 %, in different studies (Antoniou et al., 2003, Ayers et al., 2014, Bäuerle et al., 2011, Bach et al., 2020). The corresponding lifetime risk for breast cancer in BRCA2 mutation carriers is between 25 % and 45 % and for ovarian cancer between 10 % and 20 % (Antoniou et al., 2003, Ayers et al., 2014, Bäuerle et al., 2011, Bach et al., 2020). Inherited mutations in other predisposing genes are responsible for a smaller percentage of breast cancers (Beck-Peccoz et al., 2017, Beer et al., 2008). The majority of breast cancer cases cannot be attributed to specific genetic or other predisposing factors, and their development most probably represents the culmination of various environmental and genetic influences. The long-term influence of the environment of the female reproductive hormones, the estrogens and progesterone, is important in breast cancer development and has been traditionally captured by elements of the reproductive history of the patient, including age at menarche, age at menopause, number of pregnancies, age at first pregnancy and breastfeeding (Mao et al., 2023). Besides female reproductive hormones, other nuclear receptors, which are expressed in breast cancer cells, have pathogenic roles in breast cancer and may contribute to cumulative risk of development of the disease. The Androgen Receptor (AR) is expressed in sub-sets of both ER positive and ER negative breast cancers (Voutsadakis, 2016). ER positive breast cancers display a concomitant AR positivity in about 75 % to 80 % of cases, while ER negative breast cancers are AR positive in 20 % to 40 % of cases. The latter cases are mostly triple negative and many belong to a genomically luminal-like sub-set of triple negative breast cancers, with lower proliferation rates than other triple negative cancers and apocrine histology (Bolf et al., 2021, Brent, 2012). As they have no options for ER targeted therapies, AR positive, luminal and non-luminal, triple negative breast cancers may be treated with AR blocking agents, which are actively investigated in this sub-type of breast cancers (Sharifi, O’Regan, & Wisinski, 2023).

Non-steroidal receptors, VDR and TRα and TRβ are also expressed in breast cancers and transmit various biologic signals through transcription of target genes after ligation by their respective ligands, vitamin D and thyroid hormones (Cancer Genome Atlas Network, 2012, Carter et al., 2015). The VDR transcriptional programs promote cell differentiation and are tumor suppressing in breast cancer cells. Breast cancer cells express also the cytochrome enzymes CYP27B1 and CYP24A1, which participate in the conversion of the circulating form of vitamin D, 25-hydroxyvitamin D to 1a, 25-dihydroxyvitamin D, the active VDR ligand and to the 24-hydroxylated metabolite, which is inactive as a VDR ligand (Voutsadakis, 2020). Thyroid hormone receptors are similarly expressed in a sub-set of breast cancers and mediate biologic effects, following ligation by thyroid hormone. Thyroid hormones may further signal through a cell surface receptor, αvβ3 integrin (also called vitronectin receptor or thyrointegrin), which is an integrin serving as the canonical cellular receptor for vitronectin (Hercbergs, Lin, Mousa, & Davis, 2023). In addition, the thyroid axis may affect breast cancer cells through the TSH receptor, TSHR. The influence of the different components of the thyroid axis on the pathophysiology, prognosis and therapy of breast cancer will be discussed in this review. Thyroid dysfunction is a relatively common condition, affecting about 5 % of the population, with potential repercussions for breast cancer development and progression.