Exposure to Estrogens and Breast Cancer
The duration or intensity of a women’s exposure to endogenous or exogenous estrogens are the major risk factors for breast cancer. Early menarche and or late menopause increase breast cancer risk.1 Elevations in circulating estradiol levels predict the risk in developing breast cancer in the ensuing years in postmenopausal women.2-3Thus, estrogen levels can provide information independent of other known risk factors.4An estradiol level in the top quintile for example; may increase the relative risk of breast cancer three to five fold.2,3,
An index weighing several estrogens (E1,E2, E3, E1-S, E2-S) provides a higher estimate of risk than estradiol alone.5Estrogen metabolites, which do not act through the estrogen receptor (ER), are also associated with an increased risk of breast cancer.
Putative markers of long-term estrogen exposure such as bone density are also predictive. Women in the top quartile of bone density have a threefold increased risk of breast cancer; a history of fracture or height loss lowers the risk.6,7
The estradiol present in breast tissue of premenopausal women is synthesized in three sites: the ovary, extra glandular tissue, and the breast itself. After menopause, extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. In addition, the breast itself can synthesize estradiol via aromatization (via the enzyme aromatase) of androgens to estrogens (estrone sulfate), cleavage of estrone-sulfate to free estrone via the enzyme sulfatase, and conversion of estrone to estradiol via 17bOH-HSD.
Classic studies involving the infusion of radiolabeled androgens and estrogens into women provide direct evidence of both in situproduction in the breast and uptake from plasma 8 Several factors regulate in situestradiol synthesis but the most important is the degree of obesity which increases the amount of aromatase in the breast and consequently, estradiol production. The mechanism for obesity related induction of aromatase involves leptin, adiponectin and AMP-kinase which allows CRTC2to become detached from a 14-3-3 protein and enter the nucleus to increase aromatase transcription.9
Despite the fact that local estrogen synthesis may be upregulated in postmenopausal malignant breast tumors, investigators have argued that the relative role of circulating pool of estrogens may be more important for breast carcinogenesis. Studies suggest that ER mediated uptake might predominate over in situ production in the breast. A likely explanation is that the partition coefficient of non-polar estrogens favors dissolution into the fat compartment of the breast as compared to the plasma. Although local estrogen production plays an important role, the local contribution may be overridden by rapid plasma-to-tissue equilibrium, including active uptake of circulating estrogen or enhanced tissue binding.10
In spite of the dramatic fall in estrogen levels at menopause, only minor differences in breast tissue levels have been reported comparing pre- and postmenopausal women. Thus, postmenopausal breast tissue maintains concentrations of estrone (E1) that are 2 to 10 times and estradiol (E2) 10 to 20 fold higher than the corresponding plasma estrone and and estradiol levels reinforcing the importance of rapid and extensive plasma to tissue partition.11
Specifically, the tissue/plasma concentrations of E1, E2, and E1sulfate are approximately 5-6, 1,5-2 and 0.1respectively. E1, is the least polar compound (the most fat soluble) and E1 sulfate is the most polar (most water soluble). Lipophilicity and small molecule size are both predictors of rapid membrane transfer thus, the tissue/plasma estrogen concentrations can be explained by the physiochemical properties of each of the molecules.10Rapid equilibrium between plasma and tissue compartments which is supported by the highly significant correlation between plasma and tissue estrogen concentrations for E1and E2indicates that plasma estrogen levels predict benign breast tissues levels in both pre and postmenopausal women. Rapid equilibrium of breast tissue with the plasma compartment indicates that the role of local synthesis may be of minor importance.10
However, simple physiochemical properties do not explain the ratio of E1, and E2intratumoral levels. There is no significant correlation in pre- and postmenopausal women for plasma E2and intratumoral levels. This suggests that the concentration equilibrium seen for benign tissue may not apply to intratumoral levels. Studies have demonstrated that there are substantially elevated levels of E2in ER+tumors compared with normal tissue from the same breast in postmenopausal women. Additionally, tumor levels of E1are consistently lower as compared with tissue concentrations of E1in benign tissue from the same breast, independent of ER status. These finding support the conclusion that E2not only equilibrates from the plasma but is also synthesized by intratumoral reduction of E1to E2which would explain elevated levels of tumor E2as compared with benign tissue E2levels. Tumor E2concentrations are positively correlated with HSD17b7 but negatively correlated to HSD17b2 expression supporting the role of intratumoral E1to E2as the primary source of E2.10
Yet, studies have shown that in areas of breast density there is higher levels of aromatase activity than nondense areas suggesting that the increased risk of breast cancer associated with breast density is in situproduction of estrogen in the dense tissue of the breast12. Obesity has also been associated with abnormally high expression of the enzyme aromatase in the breast, increased estrogen production, and predisposition to breast hyperplasia and cancer.
- Hulka, B.S. Epidemiologic analysis of breast and gynecologic cancers. Progress in Clinical and Biological Research. 1997; 396:17-29.
- Key, T., Appleby, P., Barnes, I., Reeves, G. Endogenous Hormones and Breast Cancer Collaborative Group, Endogenous sex hormones and breast cancer in postmenopausal women; reanalysis of nine prospective studies. Journal of the National Cancer institute. 2002; 94(8):606-616.
- Kaaks, R., Rinaldi, S., Key, T. J., et al. Postmenopausal serum androgens oestrogens and breast cancer risk: The European prospective investigation into cancer and nutrition. Endocrine-Related Cancer, 2005; 12(4): 1071-1082.
- Eliassen, A. H., Missmer, S. A. Tworoger, S. S., Hankinson, S. E. Endogenous steroid hormone concentrations and risk of breast cancer: does the association vary by by a women’s predicted breast cancer risk.Journal of Clinical Oncology. 2006; 24(12):1823-1830.
- Tworoger, S., S., Rosner, B., A., Willett, W., C., et al. The combined influence of multiple sex and growth hormones on risk of postmenopausal breast cancer: a nested case control study. Breast Cancer Research. 2011; 13(5):R99
- Kuller, L. H., Cauley, J. A., Lucas, L., Cummings, S., Browner, W. S. Sex steroid hormones, bone mineral density, and risk of breast cancer. Environmental Health Perspectives. 1997; 105 (suppl 3): 593-599.
- Newcomb, P. A., Trentham-Dietz, A., Egan, K. M.et al. Fracture history and risk of breast and endometrial cancer. American Journal of Epidemiology. 2001; 153(11): 1071-1078.
- Larionov, A. A., Bernstein, L. M., Miller, W. R. Local uptake ad synthesis of oestrone in normal and malignant breast tissues. Journal of Steroid Biochemistry & Molecular Biology. 2002; 81(1): 57-64.
- Brown, K. A., Simpson, E. R. Obesity and breast cancer: Progress to understanding the relationship. (Review). (14 refs) Cancer Research. 2010; 70(1):4-7.
- Lonning, P.E., Haynes, B. P., Straume A.H., et al. Exploring Breast Cancer Estrogen Disposition: The Basis for Endocrine Manipulation (Review) .Clinical Cancer Research. 2011; 17(15):4948-4958
- Geisler J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol. 2003 Sep;86(3-5):245-253.
- Vachon, C. M., Sassano H., Ghosh, K., et al. Aromatase immunoreactivity is increased in mammographicly dense regions of the breast. Breast Cancer Research & Treatment. 2011; 125(1): 243-252.