Overexpression of c-Myc and Bcl-2 during progression and distant metastasis of hormone-treated breast cancer.

The aim of this study was to identify molecules involved in the proliferation and survival of recurrent estrogen receptor (ER)-positive breast cancer at the site of metastasis. Most studies of biomarkers are done using the initial primary breast tumor whereas pathological studies of breast cancer lesions after distant recurrence are scarce. Here we evaluated the expression of the oncogenes c-Myc and Bcl-2, mediators of estrogen-dependent proliferation and survival, during breast cancer progression and relapse after adjuvant hormonal therapy. Using a preclinical model of tamoxifen-resistant growth, we found overexpression of c-Myc in all (3/3) and of Bcl-2 in most (2/3) tamoxifen resistant-breast cancer variants. To determine whether c-Myc and Bcl-2 are expressed during breast cancer progression in the clinics we identified breast cancer patients who had received adjuvant hormonal therapy for the treatment of their localized disease and had later experienced relapse. From 583 patients who had received adjuvant hormonal therapy a total of 82 experienced recurrence. Nevertheless, only 22 patients had had a biopsy of their metastatic lesion done after relapse. Twenty-one biopsies were useful for this biomarker study. These biopsies were obtained mostly (20) from breast cancer patients who had received tamoxifen as their adjuvant hormonal therapy. One patient had received an aromatase inhibitor instead. Our results showed that almost all (20) metastatic recurrences expressed ER. Expression of c-Myc was observed in 18 out of 19 metastatic lesions scored while expression of Bcl-2 was detected in 17 out of 21 metastatic tumors. A correlation between ER expression and Bcl-2, but not with c-Myc, was found in these recurrent metastatic lesions. In addition, c-Myc expression was correlated with the nuclear grade of the metastatic lesion. Thus, the frequent expression of c-Myc and Bcl-2 in metastatic breast cancer recurrences suggests that combining hormonal therapy with strategies to block c-Myc and Bcl-2 may prevent growth of ER-positive breast cancer at the site of metastasis.

Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer.

The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src-Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.

Pilot trial of cryoprobe-assisted breast-conserving surgery for small ultrasound-visible cancers.

BACKGROUND: Stereotactic and ultrasonography-guided large core needle biopsy has replaced wire localization biopsy as the diagnostic method of choice. Lumpectomy alternatives are being sought to eliminate the need for preoperative wire localization, to facilitate easier and more accurate resection, and to decrease positive margin rates. Cryoprobe-assisted lumpectomy (CAL) was investigated as an alternative. METHODS: Patients with ultrasonographically visible breast cancers that otherwise would have required wire localization participated. Before lumpectomy, a cryoprobe (Visica; Sanarus, Pleasanton, CA) was inserted through a 3-mm skin incision and directed by ultrasonography through the center of the tumor. An ice ball was created that enveloped the tumor plus an adjacent 5-10 mm of sonographically normal breast tissue. RESULTS: Twenty-four CAL procedures were performed and all lesions were successfully localized. Mean (+/-SD) tumor size was 1.2 +/-.4 cm (range,.7-2.0 cm). Mean dimensions of the ice ball before excision were 3.9 +/-.3 cm by 2.5 +/-.5 cm, and the ice margin around the tumor was 8 +/- 2 mm. The size of the ice ball was controlled to the millimeter, and the ice ball itself provided a precise template around which to dissect. The margin re-excision rate was 5.6% among patients with an ice margin greater than 6 mm. CONCLUSIONS: CAL is a superior alternative to wire localization. Ultrasonographic visualization of the ice ball allows the size of the margin and tissue resected to be individually tailored and accurate within millimeters. The created template allows a precise lumpectomy, adding a dimension of control not previously realized with any other technology.