Molecular mechanisms of the D327N SHBG protective role on breast cancer development after estrogen exposure.

Sex Hormone-Binding Globulin, the specific carrier for sex steroids, regulates hormone bioavailable fraction and estrogen signaling system in breast cancer cells. A common single nucleotide polymorphism in the human SHBG gene results in an amino acid substitution (Asp327Asn), which introduces an additional N-glycosylation site, and is associated with reduced breast cancer risk in postmenopausal women. The frequency of this polymorphism was evaluated in a group of patients that developed breast cancer while taking hormonal replacement therapy (HRT) for menopause, an interesting model of estrogen exposure. The polymorphism frequency was significantly higher in women taking HRT that didn't develop any breast cancer than in breast cancer patients (P<0.05). To get insight into the underlying mechanisms, we compared the ability of recombinant wild type and variant (D327N) SHBG to influence estradiol effects in MCF-7 breast cancer cells. D327N SHBG was more effective than wild type protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis. This depended on the fact that D327N SHBG binding to MCF-7 cells was significantly higher than that of wild type protein. As a consequence, D327N caused a larger induction of the second messenger cAMP and a deeper inhibition of the estradiol-induced Erk (1/2) phosphorylation. Our observations, demonstrating the increased efficiency of D327N SHBG in counteracting estradiol action and a significantly higher frequency of Asp327Asn polymorphism in women not developing breast cancer after estrogen exposure, first provide evidence for the mechanism of D327N SHBG protective action.

Cost/accuracy ratio analysis in breast cancer patients undergoing ultrasound-guided fine-needle aspiration cytology, sentinel node biopsy, and frozen section of node.

We evaluated the effectiveness and the cost of axillary staging in breast cancer patients by ultrasound-guided fine-needle aspiration cytology (US-FNAC), sentinel node biopsy (SNB), and frozen sections of the sentinel node to achieve the target of the highest number of immediate axillary dissections. From January 2003 through October 2005, a total of 404 consecutive eligible breast cancer patients underwent US-FNAC of suspicious axillary lymph nodes. If tumor cells were found, immediate axillary dissection was proposed (33% of node-positive cases). If US or cytology was negative, SNB was performed. Frozen sections of the sentinel node allowed immediate axillary dissection in 31% of node-positive cases. The remaining 36% underwent delayed axillary dissection. We compared our policy with clinical evaluation of the axilla, showing better specificity of US-FNAC, the cost balanced by a 12% reduction of SNBs, and a marked reduction of unnecessary axillary dissections resulting from false-positive clinical staging. Moreover, the comparison between our policy and permanent histology of the sentinel node showed an 8% cost saving, mainly associated with the immediate axillary dissections. US-FNAC of axillary lymph nodes in breast cancer patients reliably predicts the presence of metastases and therefore refers a significant number of patients to the appropriate surgical treatment, avoiding an SNB. As cost saving to the health care system in our study is mainly related to one-step axillary surgery, US-FNAC of axillary lymph nodes and frozen section of the sentinel node generate significant cost saving for patients who have metastatic nodes.