Abstract
BackgroundMammary carcinogenesis is partly regulated by the transforming growth factor beta (TGFβ) signaling pathway. Its function in cancer progression and metastasis is highly dependent on disease stage, and it is likely modulated by the ratio of membrane-bound vs. soluble TGFβrIII (sTGFβrIII). In this prospective observational study, we assessed tissue expression and plasma levels of sTGFβrIII in healthy women, women with benign breast lesions and in early-stage breast cancer patients.MethodsIn a preliminary study, plasma sTGFβrIII levels were determined in 13 healthy women (age 19–40 years) at different phases of the ovarian cycle, and in 15 patients (age 35–75 years) at different times of the day. The main study assessed plasma concentrations of sTGFβrIII in: (i) 158 healthy women in whom breast lesions were excluded; (ii) 65 women with benign breast lesions; (iii) 147 women with newly diagnosed breast cancer classified as American Joint Committee on Cancer (AJCC) stages 0 to IIB. Completers provided blood samples before surgery and at 10–30 and 160–180 days after surgery. Plasma sTGFβrIII concentrations were determined using an indirect ELISA kit. Part of the removed tissues underwent immunohistochemical (IHC) staining and analysis of tissue TGFβrIII expression.ResultsThere appeared no relevant variations in plasma sTGFßrIII levels at different times of the day or different ovarian cycle phases. Before surgery, breast cancer patients had somewhat higher sTGFβrIII than healthy women, or those with benign breast lesions (by 14.5 and 26 ng/mL, respectively), with a tendency of larger differences at higher age. This correlated with lower expression of TGFβrIII in breast cancer vs. healthy tissue samples. At 160–180 days after surgery, plasma sTGFβrIII levels in breast cancer patients declined by 23–26 ng/mL.ConclusionsPlasma sTGFβrIII levels do not seem to relevantly vary during the day or the ovarian cycle. The coinciding higher plasma levels in newly diagnosed cancer patients than in healthy subjects and lower TGFβrIII expression in the malignant than in healthy breast tissue suggest ectodomain shedding as a source of circulating sTGFβrIII. Decline in plasma levels after tumor removal supports such a view.
Highlights
Mammary carcinogenesis is partly regulated by the transforming growth factor beta (TGFβ) signaling pathway
Preliminary study Plasma sTGFβrIII expression levels appeared similar at different ovarian cycle phases in healthy women (geometric means ratios (GMRs), at mid- and luteal phase vs. follicular phase closely around 1.0; Fig. 2a) and at different times during the day in women with breast cancer (GMRs at 13:00 and 18:00 h vs. 10:00 h closely around 1.0; Fig. 2b)
Present data suggest two potentially important conclusions: i) plasma levels of sTGFβrIII do not seem to be dependent on menstrual cycle or diurnal variations; ii) reduced TGFβrIII expression in breast cancer tissue could result from ectodomain shedding
Summary
Mammary carcinogenesis is partly regulated by the transforming growth factor beta (TGFβ) signaling pathway. Its function in cancer progression and metastasis is highly dependent on disease stage, and it is likely modulated by the ratio of membrane-bound vs soluble TGFβrIII (sTGFβrIII). In this prospective observational study, we assessed tissue expression and plasma levels of sTGFβrIII in healthy women, women with benign breast lesions and in early-stage breast cancer patients. Several non-invasive procedures, like determining the expression levels of estrogen, progesterone and epidermal growth factor (EGF) receptors, are used for risk stratification and outcome prediction in breast cancer patients [3]. Detection of circulating tumor cells has recently been proposed as an independent early sign of breast cancer metastasis, but it lacks confirmation in prospective studies [4]. Neutrophil/lymphocyte ratio has been investigated as a predictor of survival, it has proven useful only in patients without metastatic disease [5]
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