Introduction: The tumour microenvironment is hypoglycaemic, hypoxic and acidotic. This activates a stress signalling pathway: the unfolded protein response (UPR). The UPR is cytoprotective if the stressor is mild, but may initiate apoptosis if severe. Activation of the UPR in breast carcinoma is induced by microenvironmental stress such as glucose and oxygen deprivation, but may also be linked to oestrogen stimulation. It may be clinically significant as it may alter chemosensitivity to doxorubicin. Methods: 395 human breast adenocarcinomas were immunohistochemically stained for UPR activation markers (glucose-regulated protein (GRP-78 and XBP-1). A model of UPR activation in vitro by glucose deprivation of T47D breast cancer cells was developed to determine how the UPR affects cellular sensitivity to doxorubicin and 5-fluorouracil. Cytotoxicity was assessed using a colorimetric cytotoxicity assay (MTT). The effect of oestrogen stimulation and tamoxifen exposure on UPR activation by T47D cells was determined by western blotting measurement of the key UPR protein, GRP-78. Results: Expression of GRP78 and XBP-1 was demonstrated in 76% and 90% of the breast cancers, respectively, and correlated with oestrogen receptor positivity ( P =0.045 and 0.017, respectively). In vitro UPR activation induced resistance to both doxorubicin and 5-flurouracil, ( P <0.05). Oestrogen stimulation induced GRP78 and XBP1 over-expression on western blotting. Tamoxifen did not block this response and may induce UPR activation in its own right. Conclusions: The UPR is activated in the majority of breast cancers and confers resistance to chemotherapy. In vitro oestrogen stimulates UPR induction. UPR activation may contribute to breast cancer chemoresistance and interact with oestrogen response elements.

No abstract

No abstract

Breast reduction is a common surgical procedure performed by plastic and oncoplastic breast surgeons. The authors report on the incidence and management of cancer and atypical hyperplasia in breast reduction specimens from one institution over a 10-year period. All patients who underwent breast reduction surgery at Northern General Hospital, Sheffield were identified from an electronic prospective database. The histopathology reports were analyzed. Case records of all patients with significant abnormalities were retrieved and examined to identify their management and follow-up. Between October 1999 and April 2010, 1,588 patients underwent breast reduction. Nine specimens showed atypical hyperplasia (0.57%). Five cancers were detected (0.31%). Four of the five patients had normal screening mammograms 1-3 years before the reduction operation. Of these cancers, four were invasive (three lobular, one ductal) (0.25%) and one was DCIS (0.06%). A lump was felt macroscopically by the pathologist in two of the four patients with invasive cancer. The patients with DCIS did not undergo further surgery, whereas those with invasive disease underwent mastectomy (three patients) and axillary nodal staging (four patients). None of the patients with normal post-reduction breast imaging had residual cancer on histology. The incidence of occult carcinoma in breast reduction specimens is low. Patients should be counseled with regards to the possible consequences preoperatively.

We report the case of a 78-year-old Caucasian gentleman who presented with a painful swelling in the nail bed of the right middle finger. Following amputation of the right middle phalanx histopathology confirmed aggressive digital papillary adenocarcinoma (ADPA). Further surgical treatment was offered but declined. Approximately 17 months later, the patient was found to have pulmonary metastasis. ADPA is a rare neoplasm of the eccrine sweat glands, which commonly presents as a slow-growing mass between the nail bed and distal interphalangeal joint. The disease is classically aggressive with a 14% chance of metastatic spread. The chance of recurrence is 50% with no or sub-optimal treatment, which reduces to 5% following removal with adequate resection margins. This case shows a prolonged period of disease-free survival, but highlights the need for thorough and aggressive management in cases of ADPA as well as frequent and long-term follow-up.