Parathyroid hormone related protein and hypercalcaemia in breast cancer.

OBJECTIVE--To see whether parathyroid hormone related protein has a humoral role in breast cancer. DESIGN--Plasma concentrations and tumour expression of parathyroid hormone related protein were determined (by two site immunoradiometric assay and immunohistochemistry respectively) in women with breast cancer and related to the presence of bone metastases and serum calcium concentrations. SUBJECTS--Plasma concentrations of parathyroid hormone related protein were measured in 57 women with early breast cancer without apparent bone metastases, 28 women with bone metastases, and 13 women with bone metastases and hypercalcaemia. Tissue positivity for parathyroid hormone related protein was determined retrospectively in 106 primary breast tumours from women without apparent bone metastases and 72 tumours from women with bone metastases, 25 of whom subsequently developed hypercalcaemia. RESULTS--Plasma parathyroid hormone related protein concentrations were detectable (greater than 0.23 pmol/l) in 12 (92%) of the 13 hypercalcaemic patients with bone metastases compared with 10 (36%) of the 28 normocalcaemic patients with bone metastases and five (9%) of the 57 normocalcaemic patients without bone metastases. Parathyroid hormone related protein concentrations were significantly higher in hypercalcaemic than normocalcaemic patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases. Tumour staining was positive for parathyroid hormone related protein in 22 (88%) of the 25 primary breast cancers from patients with bone metastases who later developed hypercalcaemia compared with 25 (53%) of the 47 from women in this group who remained normocalcaemic and 55 (52%) of the 106 early breast cancers from women without known metastases. CONCLUSION--Tumour derived parathyroid hormone related protein may have an important humoral role in hypercalcaemia associated with metastatic breast cancer.     

Angiogenesis in male breast cancer

BACKGROUND: Male breast cancer is a rare but aggressive and devastating disease. This disease presents at a later stage and in a more advanced fashion than its female counterpart. The immunophenotype also appears to be distinct when compared to female breast cancer. Angiogenesis plays a permissive role in the development of a solid tumor and provides an avenue for nutrient exchange and waste removal. Recent scrutiny of angiogenesis in female breast cancer has shown it to be of significant prognostic value. It was hypothesized that this holds true in invasive ductal carcinoma of the male breast. In the context of male breast cancer, we investigated the relationship of survival and other clinico-pathological variables to the microvascular density of the tumor tissue. METHODS: Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Agency over a period of 26 years. Forty-seven cases of invasive ductal carcinoma of the male breast had formalin-fixed paraffin-embedded tissue blocks that were suitable for this study. All cases were reviewed. Immunohistochemical staining was performed for the angiogenic markers (cluster designations 31 (CD31), 34 (CD34) and 105 (CD105), von Willebrand factor (VWF), and vascular endothelial growth factor (VEGF)). Microvascular density (MVD) was determined using average, centre, and highest microvessel counts (AMC, CMC, and HMC, respectively). Statistical analyses compared differences in the distribution of survival times and times to relapse between levels of MVD, tumor size, node status and age at diagnosis. In addition, MVD values were compared within each marker, between each marker, and were also compared to clinico-pathological data. RESULTS: Advanced age and tumor size were related to shorter survival times. There were no statistically significant differences in distributions of survival times and times to relapse between levels of MVD variables. There was no significant difference in MVD between levels of the different clinico-pathological variables. MVD was strongly and significantly correlated between AMC, CMC and HMC for CD31, CD34, and CD105 (p < 0.01) and remained moderate to weak for VWF and VEGF. CONCLUSION: Microvascular density does not appear to be an independent prognostic factor in male breast cancer. However, the likelihood of death for men with breast cancer is increased in the presence of increased age at diagnosis and advanced tumor size. This is perhaps linked to inherent tumor vasculature, which is strongly related throughout a tumor section.     

Strategies for breast cancer therapy with antiestrogens

Current clinical research is focused upon the application of adjuvant therapy for the treatment of breast cancer. Combination chemotherapy is the most successful adjuvant therapy for premenopausal patients whereas the antiestrogen tamoxifen (1 or 2 yr) is successful in postmenopausal disease. We have developed a unifying strategy for the treatment of breast cancer. The thesis is based upon the application of continuous adjuvant therapy with tamoxifen in a low estrogen environment. Chemotherapy causes a chemical castration in premenopausal patients. In contrast, tamoxifen causes an increase in steroidogenesis. A combination of both approaches will work against each other until ovarian failure occurs. Patients should be checked for castration to provide a low estrogen environment in which tamoxifen, a competitive antagonist of estrogen action, can effectively work. Laboratory evidence using carcinogen-induced rat mammary tumor models demonstrates the efficacy of long-term therapy. Studies with the human breast cell line MCF-7 grown in athymic mice show that tamoxifen is a tumoristatic agent so that once the therapy is stopped, tumors can be regrown by estrogen administration. Patients should receive continuous tamoxifen therapy to prevent the growth-stimulating effects of adrenal steroids, environmental and phyto-estrogens.     

Current updates on precision therapy for breast cancer associated brain metastasis: Emphasis on combination therapy

Molecular and Cellular Biochemistry - Cancer therapies have undergone a tremendous progress over the past decade. Precision medicine provides a more tailored approach, making the combination of...     

RCAS1 is associated with ductal breast cancer progression

RCAS1/EBAG9 (receptor-binding cancer antigen expressed on SiSo cells/ estrogen receptor-binding fragment-associated gene 9), an estrogen-transcribed protein, has been shown to be expressed in a wide variety of cancers, including uterine, ovarian, and lung cancer cells. Soluble and membranous RCAS1 proteins may play a role in the immune escape of tumor cells by promoting T lymphocyte inhibition of growth and apoptosis. In the present report, the presence of RCAS1 was revealed in human ductal breast cancer biopsies by immunohistochemistry. Its cytoplasmic expression was exhibited in cancer cells obtained from tumor biopsies and in breast cancer cell lines. RCAS1 significantly correlated with tumor grade. In addition, RCAS1 was identified in MCF7 culture supernatants. Those observations suggest that RCAS1 is a new marker for breast cancer progression and a possible mechanism for breast cancer immune escape.     

Genetic analyses of male breast cancer in Israel

Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) germline mutations: 11 individuals from high-risk families and 20 patients unselected for family history of cancer. Two patients of the high-risk group (18.2%) displayed germline mutations: one harbored the 185delAG BRCA1 mutation, and the other the 6174delT mutation in BRCA2. None of the unselected patients displayed any mutation. In 2 patients, complete mutation analysis of the BRCA2 gene did not reveal any disease-associated mutations. We conclude that the predominant Jewish germline mutations in BRCA1/BRCA2 contribute to male breast cancer in Israel, primarily in Ashkenazi individuals with a family history of cancer.     

Novel methylation and expression markers associated with breast cancer

We have developed a modification of methylation sensitive arbitrarily primed PCR, one of the methods of differentially methylated CpG islands in cancer cells genomes screening. Seven genes undergoing abnormal epigenetic regulation in breast cancer, SEMA6B, BIN1, VCPIP1, LAMC3, KCNH2, CACNG4 and PSMF1, have been identified by this method. Methylation and loss of expression frequencies were evaluated for each of the identified genes on 100 paired (cancer/morphologically intact control) breast tissue samples. Significant frequencies of abnormal methylation were detected for SEMA6B, BIN1, and LAMC3 (38%, 18%, and 8% correspondingly). Methylation of the above genes was not characteristic for morphologically intact breast tissues. Downregulation of SEMA6B, BIN1, VCPIP1, LAMC3, KCNH2, CACNG4 and PSMF1 in breast cancer was as frequent as 44-94% by real-time PCR expression assay. The most pronounced functional alterations were demonstrated for SEMA6B and LAMC3 genes, which allows recommending their inclusion into the panels of carcinogenesis diagnostic panels. Fine methylation mapping was performed for the genes most frequently methylated in breast cancer (SEMA6B, BIN1, LAMC3), providing a fundamental basis for the development of effective methylation tests for these genes.     

Experience with reduction mammaplasty combined with breast conservation therapy in the treatment of breast cancer

As the inclusion criteria for breast conservation therapy have continued to evolve to include lower quadrant tumors, very large breasts, and central tumors, the potential for significant disfigurement after breast conservation therapy has also increased. This has led some centers to develop coordinated oncology-plastic surgery approaches to ensure both adequate cancer resection and aesthetic appearance to the breasts. The authors applied this principle to a specific group of breast cancer patients--women with macromastia--who would benefit from reduction mammaplasty. Eleven women were identified from the senior author's (S.L.S.) reconstructive practice who underwent breast conservation therapy followed by breast reconfiguration and bilateral reduction mammaplasty. Preoperative brassiere sizes ranged from 34D to 46D. All women had immediate reduction after frozen sections from the lumpectomy/partial mastectomy margins were determined to be negative. A total of 22 reduction mammaplasties were performed (eight free-nipple grafts, five inferior pedicle flaps, seven superomedial pedicle flaps, and two superolateral flaps) and an average of 1085 g was removed per breast. All patients underwent radiation therapy postoperatively. There were eight minor complications in six patients (one hematoma, one keloid, one radiation burn, two cases of nipple hypopigmentation, and three cases of fat necrosis). After an average of 24 months' follow-up, there were no local recurrences and one death from distant metastasis. Seven of the 11 patients were available and agreed to rate their aesthetic satisfaction on the basis of a scale from 1 to 4, with 4 being the best. The mean satisfaction score was 3.3. Aesthetic outcomes before radiation therapy and after radiation therapy were evaluated by a panel of plastic surgery residents blinded to the purpose of the study. Using a scale of 1 to 4, the aesthetic mean before radiation therapy was 2.9 and the aesthetic mean after radiation therapy was 3.03. By combining breast conservation therapy with breast reconfiguration or reduction in large-breasted women, multiple benefits are derived. Larger segmental or partial mastectomies can be performed without disfigurement risk, ensuring adequate surgical margins. Immediate reconfiguration of the breast with reduction of the contralateral side creates symmetric, aesthetically pleasing breasts; allows contralateral breast tissue to be evaluated; and spares women from undergoing a second operative procedure. Such a coordinated program gives women an important boost, both physically and psychologically, during management of their breast cancer.     

Plasma estrogens and androgens in male breast cancer

Androstenedione, estrone, estradiol-17β, estriol and testosterone concentrations have been measured by radioimmunoassay in plasma of 17 human males affected by breast cancer. The mean values of estrone, estradiol-17β, and estriol in male breast cancer were significantly higher than in normal controls of comparable age. Androstendione and testosterone were in normal range.Orchidectomy. performed in 3 subjects, decreased the levels of estradiol-17β, but to a lesser extent those of estrone and estriol.     

Triple-negative breast cancer and radiation therapy

BackgroundThis study aimed to review specific indications of radiation therapy for triple-negative breast cancer (TNBC), and to introduce the hypothesis of TNBC as an independent predictor for postmastectomy radiation therapy (PMRT).Materials and methodsTwo reviewers independently searched two electronic databases (Pubmed and Embase), with the inclusion dates of January 2000 to December 2021, for the following terms: “mastectomy” or “breast conserving surgery” or “lumpectomy”, and “radiation” or “radiotherapy”, and “triple negative” and “recurrence”. All evidence was explored by two reviewers, then organized into a narrative review considering grades of recommendation.ResultsPatients with TNBC are candidates for breast conserving surgery (grade of recommendation B). Postoperative whole-breast irradiation must be offered following breast conserving surgery (grade of recommendation A). Do not omit postoperative radiation therapy in older patients with TNBC (grade of recommendation B). Do not use partial-breast irradiation in patients with TNBC (grade of recommendation B). Postmastectomy radiation therapy should be offered for women with T3–T4 or node-positive TNBC, for any number of positive nodes (grade of recommendation A). Radiation therapy following mastectomy might also benefit patients with T1–T2 node-negative TNBC (grade of recommendation B). For patients treated with neoadjuvant systemic therapy, radiation therapy indication is based on pretreatment features. Retrospective studies suggest that residual TNBC is sensitive to radiation therapy to optimize locoregional control (grade of recommendation C).ConclusionsPostoperative radiation therapy should be offered for most patients with TNBC. Upcoming studies, preferably prospective randomized trials, should evaluate the indications of radiation therapy, especially in the context of novel systemic treatments.     

Effect of curcumin-nanoemulsion associated with photodynamic therapy in breast adenocarcinoma cell line

Curcumin, a natural compound has several antineoplastic activities and is a promising natural photosensitizer used in photodynamic therapy. However, its low solubility in physiological medium limit the clinical use of curcumin. This study aimed to analyze the action of curcumin-nanoemulsion, a new and well-designed Drug Delivery System (DDS+) molecule, used as a photosensitizing agent in photodynamic therapy in an in vitro breast cancer model, MCF-7 cells. The empty nanoemulsion fulfils all necessary requirements to be an excellent DDS. Furthermore, the use of curcumin-nanoemulsion in photodynamic therapy resulted in a high phototoxic effect after activation at 440?nm, decreasing to <10% viable tumor cells after two irradiations and increasing the reactive oxygen species (ROS) production. The use of curcumin-nanoemulsion associated with photodynamic therapy resulted in an increase in the levels of caspase 3/7 activity for the studied MCF-7 cell model, indicating that this therapy triggers a cascade of events that lead to cell death, such as cellular apoptosis. In conclusion, curcumin-nanoemulsion proved to be efficient as a photosensitizing agent, had phototoxic effects, significantly decreased the proliferation of MCF-7 cells and stimulating the ROS production in combination with photodynamic therapy, so, this formulation has a great potential for use in treatment of breast cancer.     

Cytologic diagnosis of male breast cancer with nipple discharge. A case report

The cytologic findings in a nipple discharge from a male patient with breast cancer are described. Malignant epithelial cells and cell clusters believed to be derived from ductal carcinoma were observed. The subsequent mastectomy specimen contained a ductal carcinoma with minute foci of stromal invasion.