Hormones and breast cancer : aspects on receptor expression and metabolism

Breast cancer is the most common malignancy among women in the western world. Sex steroid hormones are implied as risk factors but endocrine regimens are also used in the therapy of breast cancer. Current knowledge about the endocrine and metabolic effects of different treatments is incomplete. Although the estrogen receptor (ER) was discovered nearly 40 years ago, a better understanding of its complex role in cellular function is important.

This clinical and experimental study in women with primary breast cancer has shown that: Immunocytochemical analyses of ER and the progesterone receptor (PR) in fine needle aspiration (FNA) biopsies display a good concordance with established enzyme immunoassays based on cytosol homogenates. Concordance in a material of 967 tumors was about 80% and the correlation highly significant (p<0.001). Non-invasive FNA requires minimal amounts of tumor material and may be a useful tool to evaluate biological parameters in the management of breast cancer.

Tamoxifen and megestrol acetate (MA) will induce profound and distinct metabolic differences in postmenopausal women with breast cancer. During two years of follow up (n=50) tamoxifen induced suppression of androgens and IGF-I and an increase of total cortisol and the estrogen-sensitive liver proteins SHBG and CBG. In contrast, during MA there was an increase in IGF-I and a dramatic adrenal suppression. Changes in hormone levels, growth factors and plasma proteins could relate to long term risks and quality of life. Metabolic effects should be evaluated when endocrine therapies are introduced.

The increase of SHBG during treatment with the estrogen agonist tamoxifen seems to reflect ER content in tumor tissue. The individual values for SHBG (n=45) showed a highly significant correlation (rs 0.44; p<0.01) with ER content in tumor tissue. This correlation between two biologic markers could represent a constitutional characteristic. It would be of clinical importance to be able to identify women with a high estrogen sensitivity.

The expression of the two ER subtypes alpha and B differs between normal and malignant breast tissue. In paired samples collected from 37 women there was in cancerous tissue a significant suppression of the inhibitory form ERbeta (p=0.001) and a marked decrease of the ERbeta/ERalpha ratio (p<0.02). These findings in human tissue are in agreement with previous data from cell cultures and animal experiments and may relate to breast carcinogenesis.

The expression of PR in tumor tissue is increased during postmenopausal hormone therapy. This finding could relate to differences in breast cancer risk between combined estrogen/progestogen and estrogen alone.

The mammary stroma has an important role to modulate the epithelial breast cell response to sex steroid hormones. We found a remarkable difference in stromal staining for Syndecan-1 between normal and malignant breast tissue. Redistribution of this heparan sulphate proteoglycan from the epithelium and the dramatic increase of Syndecan-1 in cancerous stroma may reflect the natural history of breast cancer.

Specific and targeted interventions with a minimum of acute and late side effects are needed in the care of women with breast cancer. True progress and tailored therapies will need an improved understanding of both the tumor cell and its environment. Not only antitumoral efficacy but also treatment effects in other organs and tissues should be explored.

List of scientific papers

I. Lofgren L, Skoog L, von Schoultz E, Tani E, Isaksson E, Fernstad R, Carlstrom K, von Schoultz B (2003). Hormone receptor status in breast cancer - a comparison between surgical specimens and fine needle aspiration biopsies. Cytopathology. 14(3): 136-42.
https://doi.org/10.1046/j.1365-2303.2003.00054.x

II. Lofgren L, Wallberg B, Wilking N, Fornander T, Rutqvist LE, Carlstrom K, von Schoultz B, von Schoultz E (2004). Tamoxifen and megestrol acetate for postmenopausal breast cancer: diverging effects on liver proteins, androgens, and glucocorticoids. Med Oncol. 21(4): 309-18.
https://doi.org/10.1385/MO:21:4:309

III. Lofgren L, von Schoultz E, Fernstad R, von Schoultz B, Carlstrom K (2006). Are estrogen receptor content cancer and effects of tamoxifen on sex hormone-binding globulin markers for individual estrogen sensitivity? Journal of Steroid Biochemistry and Molecular Biology. 99. [Accepted]
https://doi.org/10.1016/j.jsbmb.2005.11.010

IV. Lofgren L, Sahlin L, von Schoultz B, Fernstad R, Skoog L, von Schoultz E (2006). Expression of sex steroid receptor subtypes in normal and malignant breast tissue - a pilot study in postmenopausal women. Acta Oncologica. [Accepted]
https://doi.org/10.1080/02841860500371865

V. Lofgren L, Sahlin L, von Schoultz B, Fernstad R, Skoog L, von Schoultz E (2006). Expression of Syndecan-1 in paired samples of normal and malignant breast tissue from postmenopausal women. [Manuscript]