The breast and ovarian cancer susceptibility gene (BRCA1) is a tumor suppressor gene discovered in 1990, and its pathogenic variants are associated with the development of early-onset breast, ovarian and other malignancies. It is known that the BRCA1 gene is involved in a variety of biological pathways, including DNA damage repair, genome stability, and cell growth and replication. Its germline pathogenic variants also make breast and ovarian cancer heritable tumors and increase the risk of breast or ovarian cancer in carriers by 10-20 times compared with the general population. At the same time, women with BRCA1 gene mutations are at increased risk of fallopian tube cancer, pancreatic cancer, gastrointestinal cancer, and melanoma, men are at increased risk of breast cancer and prostate cancer.

The relationship between BRCA1 gene and cancer has been widely studied, but related studies and experiments have shown that BRCA1 gene is not only closely related to tumorigenesis, but also related to some steroid hormone activity and lipogenesis, including diabetes and metabolic syndrome.

1. BRCA1 inhibits the expression of insulin-like growth factor 1 receptor Insulin-like growth factors (IGFs) are a class of multifunctional cell proliferation regulators, which play an important role in the development and maturation of the mammary gland, are also a key factor in the occurrence and development of breast cancer. IGF1R is the cell surface insulin-like growth factor 1 receptor. Epidemiological analyses conducted over the past 25 years have identified IGF1 as a risk factor for breast cancer. Studies have shown that wild-type BRCA1 breast cancer cells inhibit the gene transcription and promoter activity of IGF1R, while mutant BRCA1 cannot inhibit IGF1R promoter activity.

Since the transcriptional activity of BRCA1 is strongly dependent on the status of the tumor suppressor gene p53. Thus, BRCA1 can be transcribed in p53 gene-expressing cells, but not in mutant-deleted p53 cells.

2. Metabolic role of BRCA1

Obesity and hyperinsulinemia are well-established risk factors for breast cancer. Wild-type BRCA1 induced a number of metabolic modifications, including marked repression of glycolysis. Compared with BRCA1 mutants, all glycolytic indicators of BRCA1 wild type were greatly reduced, and the five major enzymes of this glycolytic pathway, including HK2 and PFKFB3, as well as pyruvate and lactate, were down-regulated by BRCA1 transfection. On the other hand, tricarboxylic acid (TCA) cycle and oxidative phosphorylation are activated in BRCA1-expressing cells. Studies have shown the potential role of BRCA1 in the regulation of lipogenesis and energy metabolism: Wild-type BRCA1 inhibits acetyl-CoA carboxylase (ACCA), a key enzyme in fatty acid synthesis, while mutant BRCA1 makes this .This inhibitory effect is reduced, resulting in an increase in fat. The mitogenic response to IGF1 was reduced in breast cancer cells at physiological glucose values, but not significantly different in normal mammary epithelial cells. Therefore, it is reasonable to assume that normal glucose concentrations promote BRCA1 inhibition of IGF1 metabolism. A corollary can be drawn from this: maintaining physiological levels of glucose can improve BRCA1 function and delay breast cancer progression.

3. Interaction of BRCA1 with steroid hormones

Earlier studies have identified interactions between BRCA1 and many steroid hormone functions, including estrogen receptor-alpha (ERα) and androgen receptor (AR). BRCA1 inhibits estrogen-induced ERα transcriptional activity in breast and prostate cancer cells, whereas cancer-associated BRCA1 mutant cells do not appear to inhibit ERα activity. On the other hand, estrogen is able to enhance BRCA1 expression, possibly as a result of the mitogenic activity of estrogen. Studies have shown that the direct effect of estrogen is that estradiol directly stimulates BRCA1 promoter activity.

Unlike BRCA1-related tumors, where regulation of ERα signaling by BRCA1 is important in sporadic carcinogenesis, such tumors are often ERα-positive and frequently exhibit loss of BRCA1 expression. Loss of BRCA1 may result in a lack of antagonistic estrogen stimulation in mammary epithelial cell proliferation. In a study of 228 women screened for familial ovarian cancer in the UK, the effect of BRCA1/2 mutations on steroid hormone activity was assessed by examining endometrial thickness on each menstrual cycle day as an indicator of hormone regulation. In addition, estradiol and progesterone titers were measured on the same day. The authors report that BRCA1/2 mutation carriers are exposed to increased levels of both steroid hormones. The higher values of estradiol in mutation carriers are consistent with a potential carcinogenic effect of this hormone in the ovary.

Evidence for a functional interaction between BRCA1 and androgens is shown experimentally. BRCA1 regulates IGF1R differently in AR-negative and AR-positive prostate cancer cells. BRCA1 is expressed at relatively high levels in prostate cancer compared to low BRCA1 levels in normal prostate epithelium. Furthermore, in AR-negative prostate cancer cells, IGF1R and BRCA1 expression levels were negatively correlated, while in AR-positive cells, they were positively correlated. Finally, co-transfection experiments showed that BRCA1 expression enhanced AR transcriptional activity. The above analyses revealed a new mechanism by which IGF1R and AR stimulate prostate cancer, and further supported the role of IGF1R and AR, BRCA1 as targeting markers in prostate cancer.

4. Conclusion

The above studies highlight an important emerging role for BRCA1 as a metabolic and endocrine regulator. Although BRCA1 was discovered due to its role in cancer biology and its genomic activity, increasing evidence suggests that BRCA1 exhibits a range of roles that do not fall into the class of classical cancer-associated roles. Among other physiological activities, BRCA1 has been shown to induce metabolic regulation in breast cancer cells, is an important step in the control of adipogenesis pathways, interacts with IGF1, estrogens and androgens and plays a key role in energy metabolism, and its interaction mechanism also requires to be explored further. In conclusion, a better understanding of the complex physics and functions between BRCA1 and hormones and metabolic pathways will allow us to better understand the extensive effects and mechanisms of BRCA1 gene on life activities and tumorigenesis, thereby guiding the treatment of more diseases and benefiting a wider range of crowd.

Reference：

1. Haim Werner.BRCA1：An Endocrine and Metabolic Regulator.Front Endocrinol (Lausanne).2022 Mar 31.v.13; 2022

2.2.Lann D, LeRoith D. The Role of Endocrine Insulin-Like Growth Factor-I and Insulin in Breast Cancer. J Mamm Gland Biol Neoplasia (2008) 13:371–9. doi: 10.1007/s10911-008-9100-x

3.3.Koobotse M, Holly J, Perks C. Elucidating the Novel BRCA1 Function as a Non-Genomic Metabolic Restraint in ER-Positive Breast Cancer Cell Lines. Oncotarget (2018) 9:33562–76. doi: 10.18632/oncotarget.26093

4.4.Koobotse MO, Schmidt D, Holly JMP, Perks CM. Glucose Concentration in Cell Culture Medium Influences the BRCA1-Mediated Regulation of the Lipogenic Action of IGF-I in Breast Cancer Cells. Int J Mol Sci (2020) 21:8674. doi: 10.3390/ijms21228674

5.5.Widschwendter M, Rosenthal AN, Philpott S, Rizzuto I, Fraser L, Hayward J, et al. . The Sex Hormone System in Carriers of BRCA1/2 Mutations: A Case-Control Study. Lancet Oncol (2013) 14:1226–32. doi: 10.1016/S1470-2045(13)70448-0

6.6.Schayek H, Haugk K, Sun S, True LD, Plymate SR, Werner H. Tumor Suppressor BRCA1 is Expressed in Prostate Cancer and Control IGF1-R Gene Transcription in an Androgen Receptor-Dependent Manner. Clin Cancer Res (2009) 15:1558–65. doi: 10.1158/1078-0432.CCR-08-1440

7.7.Moreau K, Dizin E, Ray H, Luquain C, Lefai E, Foufelle F, et al. . BRCA1 Affects Lipid Synthesis Through its Interaction With Acetyl-Coa Carboxylase. J Biol Chem (2006) 281:3172–81. doi: 10.1074/jbc.M504652200