IGFBP-3 can either inhibit or enhance EGF-mediated growth of breast epithelial cells dependent upon the presence of fibronectin.

Progression of breast cancer is associated with remodeling of the extracellular matrix, often involving a switch from estrogen dependence to a dependence on EGF receptor (EGFR)/HER-2 and is accompanied by increased expression of the main binding protein for insulin-like growth factors (IGFBP-3). We have examined the effects of IGFBP-3 on EGF responses of breast epithelial cells in the context of changes in the extracellular matrix. On plastic and laminin with MCF-10A normal breast epithelial cells, EGF and IGFBP-3 each increased cell growth and together produced a synergistic response, whereas with T47D breast cancer cells IGFBP-3 alone had no effect, but the ability of EGF to increase cell proliferation was markedly inhibited in the presence of IGFBP-3. In contrast on fibronectin with MCF-10A cells, IGFBP-3 alone inhibited cell growth and blocked EGF-induced proliferation. With the cancer cells, IGFBP-3 alone had no effect but enhanced the EGF-induced increase in cell growth. The insulin-like growth factor-independent effects of IGFBP-3 alone on cell proliferation were completely abrogated in the presence of an EGFR, tyrosine kinase inhibitor, Iressa. Although IGFBP-3 did not affect EGFR phosphorylation [Tyr(1068)], it was found to modulate receptor internalization and was associated with activation of Rho and subsequent changes in MAPK phosphorylation. The levels of fibronectin and IGFBP-3 within breast tumors may determine their dependence on EGFR and their response to therapies targeting this receptor.

Therapeutic mammoplasty allows for clear surgical margins in large and multifocal tumours without delaying adjuvant therapy.

INTRODUCTION: Therapeutic mammoplasty (TM) is suggested to have a number of advantages by comparison to standard breast conservation surgery in selected patients, however, data to support such assertions are sparse and outcomes remain uncertain. We assess the ability of TM to achieve some of its suggested benefits, specifically obtaining clear surgical margins (CSM) around large or multifocal tumours, and examine whether TM is associated with delay in administering adjuvant therapies. METHOD: Data were extracted from a prospectively maintained database on all patients undergoing TM over 8 years. Key oncological outcomes and time to initiation of adjuvant therapies were recorded. RESULTS: Sixty eight patients underwent TM, sixty two for invasive disease and six for in-situ disease only. Tumour size ranged from 3 mm to 85 mm. Twenty-one (30.8%) patients received neo-adjuvant therapy, with 15 (22.0%) receiving chemotherapy and six (8.8%) receiving endocrine therapy prior to surgery. CSM were obtained in 65 patients (95.6%). Where margins were involved, two were due to Ductal Carcinoma in situ and one from undiagnosed invasive lobular cancer, resulting in one wider excision and two completion mastectomies. Radiotherapy was delayed in one patient with delayed wound healing. No local recurrence has been recorded. CONCLUSION: These data support the ability of TM to consistently achieve CSM around large and multifocal tumours in selected patients, with acceptable local control and minimal morbidity and delay in adjuvant therapies.