Increased 5α-reductase type 2 expression in human breast carcinoma following aromatase inhibitor therapy: the correlation with decreased tumor cell proliferation.

Tumor cell proliferation and progression of breast cancer are influenced by female sex steroids. However, not all breast cancer patients respond to aromatase inhibitors (AI), and many patients become unresponsive or relapse. Recent studies demonstrate that not only estrogens but also androgens may serve as regulators of estrogen-responsive as well as estrogen-unresponsive human breast cancers. However, the mechanism underlying these androgenic actions has remained relatively unknown. Therefore, in this study, we evaluated the effects of AI upon the expression of enzymes involved in intratumoral androgen production including 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5), 5α-reductase types 1 and 2 (5αRed1 and 5αRed2) as well as androgen receptor (AR) levels and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). Eighty-two postmenopausal invasive ductal carcinoma patients were enrolled in CAAN study from November 2001 to April 2004. Pre- and post-treatment specimens of 29 cases were available for this study. The status of 17ßHSD5, 5αRed1, 5αRed2, and Ki67 in pre- and post-treatment specimens were evaluated. The significant increments of 5αRed2 as well as AR were detected in biological response group whose Ki67 LI decreased by more than 40% of the pre-treatment level. This is the first study demonstrating an increment of 5αRed2 and AR in the group of the patients associated with Ki67 decrement following AI treatment. These results suggest that increased 5αRed2 and AR following AI treatment may partly contribute to reduce the tumor cell proliferation through increasing intratumoral androgen concentrations and its receptor.

Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients.

BACKGROUND: Aromatase inhibitor (AI) has been established as an effective endocrine therapy in estrogen receptor (ER)-positive postmenopausal breast cancer patients. Our recent proteomic analysis demonstrated that ten proteins were significantly altered in their expression levels before and after the therapy in the patients receiving neoadjuvant AI. Among these newly identified proteins, heat-shock protein 70 (HSP-70) was the most significantly correlated with both clinical and pathological responses. Therefore, in this study, we further evaluated the significance of this HSP-70 alteration using immunohistochemistry. MATERIALS AND METHODS: A total of 32 patients treated with neoadjuvant exemestane or letrozole in whom pre- and post-treatment tumor tissues were available were included. Immunohistochemical evaluation of ER, progesterone receptor (PgR), Her-2, Ki-67 and HSP-70 was performed. Results obtained were compared to both clinical and biological responses of the patients. RESULTS: The majority of the patients responded to treatment (16 patients with partial response, 14 with stable disease and 2 with progressive disease). The means of ER, Ki-67 and HSP-70 were significantly different between treatment responders and non-responders. Decrement of HSP-70 and Ki-67 after AI treatment and pretreatment Ki-67 labeling index of >10% tumor cells were significantly associated with clinical responsiveness to AI treatment (p<0.0001). There was a significant positive correlation between changes of HSP-70 and Ki-67 before and after the therapy. CONCLUSION: Decrement of HSP-70 in breast carcinoma cells plays important roles in therapeutic mechanisms of AIs through suppressing tumor cell proliferation in breast cancer patients.

Changes in protein expression after neoadjuvant use of aromatase inhibitors in primary breast cancer: a proteomic approach to search for potential biomarkers to predict response or resistance.

OBJECTIVE: Aromatase inhibitors (AI) have been established as a useful hormonal therapy in hormone receptor-expressing breast carcinoma. However, changes in tumor protein expression after exposure to AIs are not necessarily well understood. These changes may provide insight into how breast carcinomas respond or develop into a state of resistance towards AIs, and lead to the discovery of potential biomarkers to predict treatment responses. METHODS: Post-menopausal breast cancer patients were recruited to receive 3 months treatment with neoadjuvant AI. Carcinoma tissues were collected before and after the use of AIs and protein expression profiles were compared using two-dimensional gel electrophoresis. Protein spots with different levels of expression were identified using mass spectrometry. RESULTS: A total of 14 matched pairs of tumor tissues were collected. Both up-regulated and down-regulated proteins were selected and identified as follows: heat shock protein 70 protein 2; Cyclin M3, alpha 1 antichymotrypsin precursor; carbonic anhydrase I, cancer antigen 1; SOBP protein; Rho GDP dissociation inhibitor alpha; glyoxalase I with benzyl glutathione inhibitor; lipid-free human apolipoprotein A-I and RAB4A member RAS oncogene family. Among these proteins, heat shock protein 70 demonstrated the most significant positive correlation with clinical response of the patients. CONCLUSION: After neoadjuvant use of AI, heat shock protein 70 demonstrated the most consistent phenotypic consistency in both up-regulated and down-regulated protein expression levels among the 14 studied pairs of tumor tissue. Other proteins worthwhile exploring were also identified in this study. These proteins could serve as potential predictors for AI response.

Presence of extensive intraductal component in patients undergoing breast conservative surgery predicts presence of residual disease in subsequent completion mastectomy.

BACKGROUND: Local recurrence remains a serious problem among patients undergoing breast conservative surgery. This study aimed at identifying risk factors for residual disease after breast conservative surgery. METHODS: This retrospective study was based on patients with invasive breast cancer who have received breast conservative surgery and subsequent completion mastectomy. All patients had a clear resection margin in the initial operation. We analyzed the association between the presence of residual disease during completion mastectomy and the following risk factors: T staging, young age, and presence of extensive intraductal component (EIC), a close margin, lymphovascular permeation (LVP), positivity of estrogen receptor, progesterone receptor, and c-erbB-2. RESULTS: Residual disease was encountered in 21 (45.7%) of 46 patients; EIC was present in 28 patients (60.9%), of whom 17 had residual disease. Presence of EIC during breast conservation surgery was associated with a higher risk of residual disease during completion mastectomy (P = 0.011). Other variables were not statistically significant risk factors for presence of residual disease. No local recurrence was recorded in our cohort, and the disease-free survival and overall survival after completion mastectomy were similar for patients who had residual disease and those who had not. CONCLUSIONS: The presence of EIC is a significant risk factor for residual disease in patients after breast conservative surgery. Our findings may suggest the indicated value of completion mastectomy in patients with EIC during initial breast conservative surgery to decrease the risk of subsequent local failure.