لخّصلي

The effect of hormones on tumorigenesis and tumor progression, particularly the function of the estrogen signal pathway in breast cancer, has been widely discussed. However, the pathogenesis and progression of breast cancer remains unclear. Furthermore, the specific functions of other hormones, including FSH and LH, have not been fully elucidated with regard to the progression of breast cancer. The present study analyzed 187 post-menopausal breast cancer patients to determine whether or not the serum hormonal levels of FSH, LH, P and PRL were associated with the expression of two key molecular markers, Ki67 and Her-2. Premenopausal patients were excluded as their hormonal levels are affected by their physiological cycle and thus their basic hormonal level is difficult to determine in the surgery department of the hospital. The serum FSH levels differed between the Her-2+ and Her-2− patients, and higher FSH levels were identified in the Her-2+ patients. A higher serum FSH level was also identified in patients with high Ki67 expression (IHC, 3+). The serum LH level exhibited no significant difference based on Her-2 expression, but a higher serum LH level was observed in the patients with a high Ki67 (IHC, 3+).
FSH and LH belong to a family of glycoprotein hormones, which also include placental hCG and thyroid-stimulating hormone (TSH). FSH and LH are key regulators of reproductive function in the endocrine system and regulate steroidogenesis and gametogenesis in the ovary and the testis. FSH stimulates follicular cell activity through FSHR. FSHR expression is restricted to the sterol cells in the testis and the granulose cells in the ovary (26,27). FSHR expression has been identified in cancer cells. However, the exact function of gonadotropin and its molecular mechanism in the formation and development of tumors has not yet been fully characterized.
The FSH and LH receptors belong to the super family of G protein-coupled receptors (GPCRs). However, these hormones are unique as they have a large ectodomains that contain a leucine-rich repeat, which is significant for ligand binding. FSHR expression has been identified in various cancer cells, but rarely in breast cancer tissues or cell lines. However, numerous leucine-rich GPCRs (LGRs) have been identified in the human genome (28). In addition to FSHR, other LGR subgroups are able to transmit signals from gonadotropins (28,29). The expression of leucine-containing GPCRs should be detected in breast cancer as FSH is widely distributed in the cytoplasm of epithelial cells in breast cancer, in which higher levels of FSH are observed in benign mammary tumors and breast cancer compared with normal cells (30). Further studies are required to determine whether or not FSH stimulates Her-2 expression and cell proliferation by the LGR subgroup. FSH may function in the malignant transformation of breast cancer via a specific receptor, but not the traditional FSHR.
Furthermore, the menopause affects Her-2 expression in breast cancer (31). One study focused on FSH and Her-2 in breast cancer (32), while certain studies have revealed that FSH stimulates Her-2 expression via specific signaling pathways, including cAMP, in ovarian cancer (22,33,34). In the present study, patients with high Ki67 expression (IHC, 3+) exhibited higher serum FSH and LH levels. A total of 10 ng/ml FSH was able to upregulate the expression of Her-2 and Ki67 at the transcriptional level in 24 h in a breast cancer cell line in vitro (data not shown). Thus, gonadotropins are able to directly or indirectly promote cell proliferation in breast cancer.
To determine whether or not FSH is an independent prognostic marker, the association between FSH or LH and the overall survival (OS) or relapse-free survival (RFS) of the patients was evaluated in the present study. However, the data in this study was acquired from patients who were diagnosed with breast cancer within the past 5 years. Thus, OS/RFS could not be sufficiently evaluated in the study. Future studies with regard to this topic are required.
In conclusion, in the present cases of post-menopausal breast cancer, the Her-2+ patients were observed to have a higher serum FSH level than the Her-2− patients. The patients with high Ki67 expression (IHC, 3+) exhibited higher serum FSH and LH levels. In addition to E2, FSH and LH may have significant functions in breast cancer progression.