In the present study, we aimed to preincubate MCF-10A cells with pioglitazone and/or serum-rich growth media and to determine adhesive and non-adhesive interactions of the preincubated MCF-10A cells with BT-474 cells. For this purpose, the MCF-10A cells were preincubated with pioglitazone and/or serum-rich growth media, at appropriate concentrations, for 1 week. The MCF-10A cells preincubated with pioglitazone and/or serum-rich growth media were then co-cultured adhesively and non-adhesively with BT-474 cells for another week. Co-culture of BT-474 cells with the preincubated MCF-10A cells, both adhesively and non-adhesively, reduced the growth of the cancer cells. The inhibitory effect of the preincubated MCF-10A cells against the growth of BT-474 cells was likely produced by increasing levels of soluble factors secreted by the preincubated MCF-10A cells into the conditioned medium, as immunoassayed by ELISA. However, only an elevated level of a soluble factor distinguished the conditioned medium collected from the MCF-10A cells preincubated with pioglitazone and serum-rich growth medium than that with pioglitazone alone. This finding was further confirmed by the induction of the soluble factor transcript expression in the preincubated MCF-10A cells, as determined using real-time PCR, for the above phenomenon. Furthermore, modification of the MCF-10A cells through preincubation did not change the morphology of the cells, indicating that the preincubated cells may potentially be injected into mammary fat pads to reduce cancer growth in patients or to be used for others cell-mediated therapy.
Percutaneous biopsy in breast cancer has been associated with an increased risk of malignant cell seeding. However, the importance of these observations remains obscure due to lack of corroborating evidence from clinical studies. We determined whether method of biopsy is associated with breast cancer survival. This hospital registry-based cohort study included 3416 non-metastatic breast cancer patients diagnosed from 1993 to 2011 in a tertiary setting. Factors associated with biopsy methods were assessed. Multivariable Cox regression analysis was used to determine the independent prognostic impact of method of biopsy. Overall, 990 patients were diagnosed by core needle biopsy (CNB), 1364 by fine needle aspiration cytology (FNAC), and 1062 by excision biopsy. Excision biopsy was significantly associated with more favorable tumor characteristics. Radiotherapy modified the prognostic impact of biopsy method (Pinteraction breast cancer, further studies are warranted.
Epidermal inclusion cyst (EIC) arising from the breast is an uncommon benign condition. We report two cases of enlarging EIC of the breast in two women in their forties. The diagnosis of this condition may not be straightforward with imaging alone if an EIC presents as an enlarging lump in the breast and mimics a benign breast lesion, most commonly a fibroadenoma or malignant lesion with benign imaging features. Excision is usually recommended for a definite histopathological diagnosis and for the prevention of potential risks of malignant transformation. Asymptomatic stable lesions do not require treatment; biopsy is unnecessary, and follow-up imaging suffices if typical sonographic and clinical findings are found.
INTRODUCTION: Malaysian women have a 1 in 20 chance of developing breast cancer in their lifetime. Sabah, formerly known as North Borneo, is part of East Malaysia with a population of 3.39 million and more than 30 ethnic groups. We conducted a 2 year prospective epidemiological study to provide unreported data of breast cancer from this part of the world and to recognise which particular group of patients are more likely to present with advanced disease.
METHODS: All newly diagnosed breast cancers seen at the Queen Elizabeth Hospital, Kota Kinabalu, from January 2005 to December 2006 were included in the study. Patient and tumour characteristics, including age, race, education, socioeconomic background, parity, practice of breast feeding, hormonal medication intake, menopausal status, family history, mode of presentation, histology, grade, stage of disease and hormonal receptors status were collected and analysed.
RESULTS: A total of 186 patients were seen. The commonest age group was 40 to 49 years old (32.3%). Chinese was the commonest race (30.6%) followed by Kadazan-Dusun (24.2%). The commonest histology was invasive ductal carcinoma (88.4%). Stages at presentation were Stage 0- 4.8%, Stage I- 12.9%, Stage II- 30.1%, Stage III- 36.6% and Stage IV- 15.6%. The estrogen and progesterone receptor status was positive in 59.1% and 54.8% of cases, respectively. 73.7% of Chinese patients presented with early cancer compared to 36.4% of the other races. Patients who presented with advanced disease were also poor, non-educated and from rural areas. 20.4% of patients defaulted treatment; most of them opted for traditional alternatives.
CONCLUSIONS: Sabahan women with breast cancer present late. Great efforts are needed to improve public awareness of breast cancer, especially among those who have higher risk of presenting with advanced disease.
Breast cancer is the most common malignancy among females in Malaysia. Attempts have been made to investigate the association between breast cancer and human leukocyte antigen (HLA) types. However, data from those previous studies are highly variable. The aim of this study is to investigate the association between HLA-A types and clinicopathological factors in breast cancer. The frequencies of HLA-A type in 59 female patients with infiltrating ductal of the breast were determined by polymerase chain reaction method. HLA-A2/A30 and A2/A31 haplotype (5.1%; P = 0.045) as well as HLA-A30 (5.1%, P = 0.045) and A31 (6.8%; P = 0.020) allele were significant higher in the patients than controls (0%). HLA-A24 allele was negatively related to lymph node metastasis (r = -0.316; P = 0.021) whereas, A26 (r = -0.430; P = 0.001) and A36 (r = -0.430; P = 0.001) alleles were negatively correlated to distant metastasis in breast cancer. Negative correlations between HLA-A26/A36 (r = -0.430; P = 0.001), A2/A11 (r = -0.276; P = 0.044), A24/A34 (r = -0.430; P = 0.001) haplotypes and distant metastasis were identified. Interestingly, Her2 expression in breast carcinoma was negatively correlated to A11/24 haplotypes (r = -0.294; P = 0.034) but positively correlated to homozygous HLA-A24 (r = 0.396; P = 0.040). In conclusion, HLA-A2, -A30 and A31 were associated with breast cancer.
We aim to identify clinicopathologic predictors for response to neoadjuvant chemotherapy and to evaluate the prognostic value of pathologic complete response (pCR) on survival in Asia. This study included 915 breast cancer patients who underwent neoadjuvant chemotherapy at five public hospitals in Singapore and Malaysia. pCR following neoadjuvant chemotherapy was defined as 1) no residual invasive tumor cells in the breast (ypT0/is) and 2) no residual invasive tumor cells in the breast and axillary lymph nodes (ypT0/is ypN0). Association between pCR and clinicopathologic characteristics and treatment were evaluated using chi-square test and multivariable logistic regression. Kaplan-Meier analysis and log-rank test, stratified by other prognostic factors, were conducted to compare overall survival between patients who achieved pCR and patients who did not. Overall, 4.4% of nonmetastatic patients received neoadjuvant chemotherapy. The median age of preoperatively treated patients was 50 years. pCR rates were 18.1% (pCR ypT0/is) and 14.4% (pCR ypT0/is ypN0), respectively. pCR rate was the highest among women who had higher grade, smaller size, estrogen receptor negative, human epidermal growth factor receptor 2-positive disease or receiving taxane-based neoadjuvant chemotherapy. Patients who achieved pCR had better overall survival than those who did not. In subgroup analysis, the survival advantage was only significant among women with estrogen receptor-negative tumors. Patients with poor prognostic profile are more likely to achieve pCR and particularly when receiving taxane-containing chemotherapy. pCR is a significant prognostic factor for overall survival especially in estrogen receptor-negative breast cancers.
A study was initiated to explore possible differences in handling telomere attrition in the most common lignant and benign tumours of the breast in Malaysian women. Infiltrating ductal carcinoma (IDC) and fibroadenoma (FA) represented the malignant and benign prototypes respectively. 29 IDC, 28 FA and 22 benign non-lesional control (BNL) breast tissue samples were analysed for telomerase activation using a Telomerase PCR ELISA kit (Boehringer Mannheim). In addition, 23 IDC, 12 FA and 14 BNL were subjected to telomere length determination with a TeloTAGGG Telomere Length Assay Kit (Roche Diagnostic GmbH, Germany), following digestion of genomic DNA by frequently cutting restriction enzymes RsaI and HinfI. Mean telomerase activity in IDC (A450nm=0.3338), but not FA (A450nm=0.0003) was significantly raised (p<0.05) compared with BNL (A450nm=0.0031). Similarly IDC (1.2 kb), but not FA (2.2 kb), showed significant telomere shortening (p<0.05) relative to BNL (2.9 kb). The findings imply that telomere attrition and telomerase activation differ between malignant and benign tumours of the breast and may be important for targeted therapy.
Eighty-six infiltrating ductal carcinoma of breast were studied by the standard avidin-biotin complex immunoperoxidase method on formalin-fixed, paraffin-embedded tissue sections, for oestrogen receptor (ER) protein and c-erbB-2 oncoprotein expression. They were categorized according to the modified Bloom and Richardson criteria into three histological grades. 21% tumours were ER positive while 44% were c-erbB-2 positive. Of ER positive tumours, 33.3% were c-erbB-2 positive whereas the c-erbB-2 positivity rate was much higher (47.1%) in ER negative tumours. Only 16% of c-erbB-2 positive tumours were ER positive while 25% of c-erbB-2 negative tumours were ER positive. This negative relationship between ER and c-erbB-2 expression was statistically significant (Mc Nemar's test, p < 0.005). The ER positivity rate did not vary significantly with histological grade. However, c-erbB-2 overexpression was significantly more prevalent in grade III tumours compared with grade I and II tumours (Chi-square test, p < 0.005). Since the c-erbB-2 oncogene has extensive structural homology to the epidermal growth factor receptor (EGFR) gene, we expect that c-erbB-2 oncoprotein would share functional similarities with EGFR leading to both loss of oestrogen receptor and poor prognosis in breast cancer. Its overexpression can be expected to relate to more aggressive tumour proliferation and may explain its correlation with high histological grade, a known indicator of aggressive cancer behaviour. As there is no indication that ER protein activity contributes to advancement in histological grade, it would appear that cellular dedifferentiation precedes ER loss during malignant transformation. It has been mooted that ER positive breast cancers which also show c-erbB-2 oncoprotein overexpression have a poorer response to hormonal therapy. The use of this parameter in the routine assessment of breast cancer patients may identify subsets of patients for more aggressive therapy.
One hundred and twelve infiltrating ductal carcinoma of breast were studied by the standard avidinbiotin complex immunoperoxidase method on formalin-fixed, paraffin-embedded tissue sections, using a monoclonal antibody to c-erbB-2 oncoprotein. The same tumours were assessed and scored according to the Bloom and Richardson criteria into three histological grades. The distribution of tumours according to grade were: 8 Grade I, 34 Grade II and 70 Grade III. Forty-three (38.4%) tumours showed positive membrane staining for c-erbB-2 oncoprotein. These comprised 7 Grade II and 36 Grade III tumours with c-erbB-2 immunopositivity rates of 20.6% and 51.4% respectively. The oncoprotein was not expressed by Grade I tumours. This study shows a good correlation between c-erbB-2 expression and histological grade, a known prognostic indicator of invasive breast carcinoma. Because the c-erbB-2 oncogene has extensive structural homology to the epidermal growth factor receptor gene, its overexpression can be expected to result in more aggressive tumour behaviour. While it may be regarded as another indicator of poor prognosis breast cancers, its value in the selection of carcinomas less responsive to hormonal therapy and those more suitable for immunotherapy than chemotherapy has been mooted but remains to be clarified.
Women's breasts are susceptible to developing cancer; this is supported by a recent study from 2016 showing that 2.8 million women worldwide had already been diagnosed with breast cancer that year. The medical care of a patient with breast cancer is costly and, given the cost and value of the preservation of the health of the citizen, the prevention of breast cancer has become a priority in public health. Over the past 20 years several techniques have been proposed for this purpose, such as mammography, which is frequently used for breast cancer diagnosis. However, false positives of mammography can occur in which the patient is diagnosed positive by another technique. Additionally, the potential side effects of using mammography may encourage patients and physicians to look for other diagnostic techniques. Our review of the literature first explored infrared digital imaging, which assumes that a basic thermal comparison between a healthy breast and a breast with cancer always shows an increase in thermal activity in the precancerous tissues and the areas surrounding developing breast cancer. Furthermore, through our research, we realized that a Computer-Aided Diagnostic (CAD) undertaken through infrared image processing could not be achieved without a model such as the well-known hemispheric model. The novel contribution of this paper is the production of a comparative study of several breast cancer detection techniques using powerful computer vision techniques and deep learning models.
Breast cancer estrogen receptor (ER) status is one of the strong additional factors in predicting response of patients towards hormonal treatment. The main aim of this study was to assess the morphological characteristics and proliferative activity using MIB-1(Ki-67) of estrogen receptor negative invasive breast ductal carcinoma (NOS type) as well as to correlate these features with clinicopathological data. We also aim to study the expression of c-erbB2 in ER negative breast tumors. High proliferative rate (MIB-1 above 20%) was observed in 63 (63.6%) of 99 ER negative tumors and that these tumors were associated with high expression of c-erbB2 (57.6%). We observed that MIB-1 is a reliable independent prognostic indicator for ER negative infiltrating ductal carcinoma in this study.
At the supramolecular level, the proliferation of invasive ductal carcinoma through breast tissue is beyond the range of standard histopathology identification. Using synchrotron small angle x-ray scattering (SAXS) techniques, determining nanometer scale structural changes in breast tissue has been demonstrated to allow discrimination between different tissue types. From a total of 22 patients undergoing symptomatic investigations, different category breast tissue samples were obtained in use of surgically removed tissue, including non-lesional, benign and malignant tumour. Structural components of the tissues were examined at momentum transfer values between q = 0.2 nm-1 and 1.5 nm-1. From the SAXS patterns, axial d-spacing and diffuse scattering intensity were observed to provide the greatest discrimination between the various tissue types, specifically in regard to the epithelial mesenchymal transition (EMT) structural component in malignant tissue. In non-lesional tissue the axial period of collagen is within the range 63.6-63.7 nm (formalin fixed paraffin embedded (FFPE) dewaxed) and 63.4 (formalin fixed), being 0.9 nm smaller than in EMT cancer-invaded regions. The overall intensity of scattering from cancerous regions is a degree of magnitude greater in cancer-invaded regions. Present work has found that the d-spacing of the EMT positive breast cancer tissue (FFPE (dewaxed)) is within the range 64.5-64.7 nm corresponding to the 9th and 10th order peaks. Of particular note in regard to formalin fixation of samples is that no alteration is observed to occur in the relative differences in collagen d-spacing between non-lesional and malignant tissues. This is a matter of great importance given that preserved-sample and also retrospective study of samples is greatly facilitated by formalin fixation. Present results indicate that as aids in tissue diagnosis SAXS is capable of distinguishing areas of invasion by disease as well as delivering further information at the supramolecular level.
Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 µM. At 11.2 µM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.
The p27 V109G polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. Peripheral blood samples were collected from 230 breast cancer patients and 200 normal and healthy women who had no history of breast disease or breast cancer. We evaluated the association between the p27 polymorphism and breast cancer risk, and clinico-pathological parameters in the population. The distribution of genotype and allele frequencies of p27 V109G polymorphism were not significantly different between the breast cancer cases and normal subjects (P=0.376). Women who were homozygous (OR=1.73; 95% CI, 0.62-4.92) or heterozygous (OR=1.26; 95% CI, 0.75-2.12) for G allele, or carriers of G allele genotype (OR=1.34; 95%, 0.83-2.16) or G allele (OR=1.36; 95% CI, 0.90-2.05) were not associated with breast cancer risk. No significant correlation was noted between G allele genotype and breast cancer risk among patients under 50 (OR=1.28; 95% CI, 0.62-2.66) or 50 years and older (OR=1.38; 95% CI, 0.71-2.66) at diagnosis. The G allele genotype was significantly associated with lymph node metastases but independent of ER status and histological grade. In conclusion, the polymorphic variant at codon 109 of p27 gene may not be a marker for determining patients' risk of developing breast cancer but it may be a potential genetic marker for poor prognosis, thereby a marker for tumor prognosis.
Expression of c-erbB3 protein was investigated in 104 primary breast carcinomas comprising nine comedo ductal carcinoma in situ (DCIS), 91 invasive ductal carcinomas and four invasive lobular carcinomas using two monoclonal antibodies, RTJ1 and RTJ2. Of the 91 invasive ductal carcinomas, seven contained the comedo DCIS component adjacent to the invasive component. An immunohistochemical technique was used to evaluate the association between expression of c-erbB3 and clinical parameters and tumour markers such as epidermal growth factor receptor (EGFR), c-erbB2, cathepsin-D and p53 in archival formalin-fixed paraffin-embedded tumour tissues. Our results indicated that RTJ1 and RTJ2 gave identical staining patterns and concordant results. It was found that the overexpression of c-erbB3 protein was observed in 67% (6/9) of comedo DCIS, 52% (44/84) of invasive ductal carcinomas, 71% (5/7) of carcinomas containing both the in situ and invasive lesions and 25% (1/4) of invasive lobular carcinomas. A significant relationship (P < 0.05) was observed between strong immunoreactivity of c-erbB3 protein and histological grade, EGFR and cathepsin-D, but not with expression of c-erbB2, p53, oestrogen receptor status, lymph node metastases or age of patient. However, we noted that a high percentage of oestrogen receptor-negative tumours (59%), lymph node-positive tumours (63%) and c-erbB2 (63%) were strongly positive for c-erbB3 protein. We have also documented that a high percentage of EGFR (67%), c-erbB2 (67%), p53 (75%) and cathepsin-D-positive DCIS (60%) were strongly positive for c-erbB3. These observations suggest that overexpression of c-erbB3 protein could play an important role in tumour progression from non-invasive to invasive and, also, that it may have the potential to be used as a marker for poor prognosis of breast cancer.
The purpose of the present study was to evaluate the association between TCF7L2 rs12255372(G/T) or rs7903146(C/T) polymorphism and breast cancer risk, and clinico-pathologic characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Malaysian population. The allele (P = 0.033) frequency of rs7903146 (T) polymorphism was significantly higher in the cancer patients than normal individuals. No significant association was demonstrated between CT (OR(adj) = 1.386; 95% CI, 0.985-1.949) or TT (OR(adj) = 1.579; 95% CI, 0.869-2.870) genotype and breast cancer risk. However, women who were carriers of T allele (OR(adj) = 1.316; 95% CI, 1.022-1.695) or T allele genotype (OR(adj) = 1.419; 95% CI, 1.027-1.960) showed significant increased risk of breast cancer. Women who were GT heterozygotes (OR(adj) = 1.329; 95% CI, 0.948-1.862) or TT homozygotes (OR(adj) = 1.574; 95% CI, 0.829-2.987), and carriers of T allele genotype (OR(adj) = 1.365; 95% CI, 0.989-1.883) or T allele (OR(adj) = 1.284; 95% CI, 0.995-1.657) were not associated with breast cancer risk. The rs7903146(T) allele genotype was significantly associated with nodal involvement (P = 0.003) but rs12255372 (T) allele genotype was not associated with the clinico-pathologic characteristics. In conclusion, our findings suggest that rs7903146 (T) variant may elevate the risk of breast cancer, thus could be a potential candidate for breast cancer susceptibility. The variant may also increase the metastatic potential of the tumor.
Triple-negative breast cancer (TNBC) is associated with high grade, metastatic phenotype, younger patient age, and poor prognosis. The discovery of an effective anti-TNBC agent has been a challenge in oncology. In this study, fifty-eight ester derivatives (DETDs) with a novel sesquiterpene dilactone skeleton were organically synthesized from a bioactive natural product deoxyelephantopin (DET). Among them, DETD-35 showed potent antiproliferative activities against a panel of breast cancer cell lines including TNBC cell line MDA-MB-231, without inhibiting normal mammary cells M10. DETD-35 exhibited a better effect than parental DET on inhibiting migration, invasion, and motility of MDA-MB-231 cells in a concentration-dependent manner. Comparative study of DETD-35, DET and chemotherapeutic drug paclitaxel (PTX) showed that PTX mainly caused a typical time-dependent G2/M cell-cycle arrest, while DETD-35 or DET treatment induced cell apoptosis. In vivo efficacy of DETD-35 was evaluated using a lung metastatic MDA-MB-231 xenograft mouse model. DETD-35 significantly suppressed metastatic pulmonary foci information along with the expression level of VEGF and COX-2 in SCID mice. DETD-35 also showed a synergistic antitumor effect with PTX in vitro and in vivo. This study suggests that the novel compound DETD-35 may have a potential to be further developed into a therapeutic or adjuvant agent for chemotherapy against metastatic TNBC.
The ER-/PR+ breast tumor may be the result of a false ER negative result. The aim of this study was to investigate whether there is a difference in patient and tumor characteristics of the ER-/PR+ phenotype in an Asian setting. A total of 2629 breast cancer patients were categorized on the basis of their age, ethnicity, tumor hormonal receptor phenotype, grade and histological type. There were 1230 (46.8%) ER+/PR+, 306 (11.6%) ER+/PR-, 122 (4.6%) ER-/PR+ and 972 (37%) ER-/PR-. ER-/PR+ tumors were 2.5 times more likely to be younger than 50 years at diagnosis (OR: 2.52; 95% CI: 1.72-3.67). Compared to ER+/PR+ tumors, the ER-/ PR+ phenotype was twice more likely to be associated with grade 3 tumors (OR:2.02; 95%CI: 1.00-4.10). In contrast, compared to ER-/PR- tumors, the ER-/PR+ phenotype was 90% less likely to be associated with a grade 3 tumor (OR: 0.12; 95%CI:0.05-0.26), and more likely to have invasive lobular than invasive ductal histology (OR: 3.66; 95%CI: 1.47-9.11). These results show that the ER-/PR+ phenotype occurs in a younger age group and is associated with intermediate histopathological characteristics compared to ER+/PR+ and ER-/PR- tumors. This may imply that it is a distinct entity and not a technical artifact.
Vascular endothelial growth factor (VEGF) is a leading factor for tumour angiogenesis and p53 protein is the product of a tumor suppressor gene. The main aim of the study was to assess the association of p53 protein with VEGF expression in breast carcinoma.