Orwik

Subcellular localization of activated AKT in estrogen receptor- and progesterone receptor-expressing breast cancers: potential clinical implications.

Activated v-AKT murine thymoma viral oncogene homolog 1 (AKT)/protein kinase B (PKB) kinase (pAKT) is localized to the plasma membrane, cytoplasm, and/or nucleus in 50% of cancers. The clinical importance of pAKT localization and the mechanism(s) con... expand abstracttrolling this compartmentalization are unknown. In this study, we examined nuclear and cytoplasmic phospho-AKT (pAKT) expression by immunohistochemistry in a breast cancer tissue microarray (n = 377) with approximately 15 years follow-up and integrated these data with the expression of estrogen receptor (ER)alpha, progesterone receptor (PR), and FOXA1. Nuclear localization of pAKT (nuclear-pAKT) was associated with long-term survival (P = 0.004). Within the ERalpha+/PR+ subgroup, patients with nuclear-pAKT positivity had better survival than nuclear-pAKT-negative patients (P < or = 0.05). The association of nuclear-pAKT with the ERalpha+/PR+ subgroup was validated in an independent cohort (n = 145). TCL1 family proteins regulate nuclear transport and/or activation of AKT. TCL1B is overexpressed in ERalpha-positive compared with ERalpha-negative breast cancers and in lung metastasis-free breast cancers. Therefore, we examined the possible control of TCL1 family member(s) expression by the estrogen:ERalpha pathway. Estradiol increased TCL1B expression and increased nuclear-pAKT levels in breast cancer cells; short- interfering RNA against TCL1B reduced nuclear-pAKT. Overexpression of nuclear-targeted AKT1 in MCF-7 cells increased cell proliferation without compromising sensitivity to the anti-estrogen, tamoxifen. These results suggest that subcellular localization of activated AKT plays a significant role in determining its function in breast cancer, which in part is dependent on TCL1B expression. collapse abstract

Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet.

Estrogen receptor alpha (ERalpha)-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors form an autoregulatory hormonal network that influences estrogen responsiveness a... expand abstractnd sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ERalpha-positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. In this study, we report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3, FOXA1, and the ERalpha:FOXA1:GATA-3 target gene GREB-1. The effects of insulin on GATA-3 and FOXA1 could be recapitulated through overexpression of T-bet in MCF-7 cells (MCF-7-T-bet). Chromatin immunoprecipitation assays revealed reduced ERalpha binding to GREB-1 enhancer regions in MCF-7-T-bet cells and in insulin-treated MCF-7 cells. MCF-7-T-bet cells were resistant to tamoxifen in the presence of insulin and displayed prolonged extracellular signal-regulated kinase and AKT activation in response to epidermal growth factor treatment. ERalpha-positive cells with intrinsic tamoxifen resistance as well as MCF-7 cells with acquired tamoxifen and fulvestrant resistance expressed elevated levels of T-bet and/or reduced levels of FOXA1 and GATA-3. Analysis of publicly available databases revealed ERalpha-positive/T-bet-positive breast cancers expressing lower levels of FOXA1 (P = 0.0137) and GATA-3 (P = 0.0063) compared with ERalpha-positive/T-bet-negative breast cancers. Thus, T-bet expression in primary tumors and circulating insulin levels may serve as surrogate biomarkers to identify ERalpha-positive breast cancers with a dysfunctional hormonal network, enhanced growth factor signaling, and resistance to hormonal therapy. collapse abstract

Expression of Forkhead-box protein A1, a marker of luminal A type breast cancer, parallels low Oncotype DX 21-gene recurrence scores.

The Oncotype DX assay is one of the molecular tests that provide predictive and prognostic information to breast cancer patients with estrogen receptor (ER)-positive and node-negative disease. This study evaluates the association of Forkhead-box prot... expand abstractein A1 (FOXA1) and GATA-binding protein 3 (GATA3) expressions with Oncotype DX recurrences scores in 77 cases of patients with ER-positive node-negative breast carcinomas diagnosed at Indiana University. The data were correlated with patient age, tumor size, histologic type, Scarff-Bloom-Richardson score, histologic grade, and progesterone receptor status. The median FOXA1 and GATA3 scores were 240 and 200, respectively. The Oncotype DX recurrence scores were low in 57%, intermediate in 30%, and high in 13% of cases. FOXA1 expression correlated negatively with Oncotype DX recurrence scores (P=0.004), and histologic type (P=0.0004). Oncotype DX recurrences score also correlated negatively with progesterone receptor (P=0.035) with 100% of progesterone receptor-negative cases having high or intermediate Oncotype DX scores. FOXA1 and GATA3 expressions correlated positively (P=0.014). The correlation between FOXA1 expression and Oncotype DX recurrence scores remained significant after adjusting for multiple comparisons and controlling for confounders such as histological type, grade, and progesterone receptor. A statistically significant correlation between the Oncotype DX recurrence scores and FOXA1 expression in our diverse cohort of ER-positive breast cancer patients was observed. We propose that this may represent a more cost-effective strategy to further risk stratify patients with good prognosis in whom chemotherapy may be omitted. To confirm these findings, further studies in a larger cohort of patients are warranted. collapse abstract

Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment.

The concept of cancer cells being hierarchically organized and arising from their own progenitor stem cells will have important implications on cancer therapy. If this hypothesis were to be true then the paucity of estrogen receptors in stem cells as... expand abstract well as their inherent drug resistance mechanisms pose a challenge to current targeted therapies. In this study, we sought to examine the prognostic relevance of ALDH1, a putative cancer stem cell marker, by immunohistochemistry. The four cohorts analyzed included an adjuvantly treated series of 245 invasive cancers, a neoadjuvantly treated series of 34 cases, and two series of 58 and 40 triple negative cases, respectively. Both tumor cell and stromal expression for ALDH1 was evaluated, where possible. Tumor cell ALDH1 expression significantly correlated only with basal-like and HER2 tumor types in the adjuvant series and tumor grade in the neoadjuvant cohort. No significant enrichment for ALDH1 positive cells was observed in the postneoadjuvant therapy specimens compared to pretreatment samples. On the other hand, high degree of stromal expression was significantly associated with best disease-free survival as well as a trend for overall survival. The association of stromal expression was confirmed in an independent cohort of triple negative cases. The novel finding is that tumor microenvironment may play a significant role in determining the prognostic impact of stem/progenitor cells in human breast tumors. collapse abstract

Differential gene expression profiling of esophageal adenocarcinoma.

BACKGROUND: Differential gene expression offers an attractive means by which to study genes that may be involved in disease development and/or progression. We performed quantitative gene expression in various stages of esophageal adenocarcinoma, trea... expand abstractted exclusively by surgery with complete 2-field lymphadenectomy, in an attempt to discern genes involved in disease progression as well as genes that may predict survival. METHODS: Gene expression profiling was accomplished by cDNA-mediated annealing, selection, extension, and ligation (DASL) assay. RNA was extracted from 89 archived formalin-fixed, paraffin-embedded esophageal adenocarcinoma tissues. DASL assay was performed with the Sentrix Universal Array (Illumina Corp, San Diego, Calif) of 502 known cancer-related genes. Bioinformatics tools were used to determine significant differential gene expression in T1-2 versus T3-4 tumors and tumors without lymph node involvement (N0) versus tumors with lymph node involvement (N+). Gene expression was also correlated with overall survival. RESULTS: Twenty-one genes were overexpressed in T1-2 compared with T3-4 tumors (false discovery rate of 0). Underexpression of 1 gene was seen in N+ compared with N0 tumors (false discovery rate of 0). For overall survival, underexpression of 9 genes correlated with long survival. CONCLUSIONS: Using differential gene expression of 502 known cancer genes, we identified genes that may be involved at various stages in the progression of esophageal adenocarcinoma. We also identified genes that may correlate with prolonged survival and, thus, may serve as prognostic markers. These findings may provide further insight into the mechanisms of development and/or progression of esophageal adenocarcinoma. Prospective studies are needed to verify the prognostic value of these genes. collapse abstract

COX-2 expression does not correlate with microvessel density in breast cancer.

BACKGROUND: Cyclooxygenase-2 (COX-2), implicated in carcinogenesis and tumour progression in many cancers including breast cancer, is hypothesised to cause progression by promoting angiogenesis. The exact mechanism of such action is not known and the... expand abstract clinical evidence of such interaction is weak. We studied COX-2 expression and microvessel density (MVD) in malignant breast tissues. METHODS: COX-2 expression was analysed by immunohistochemistry in 89 breast cancer cases. MVD was assessed by CD31 immunohistochemistry using the Chalkey count method. COX-2 expression and MVD data were correlated with each other and with other prognostic factors. RESULTS: COX-2 expression, observed in 70 (79%) cases, correlated positively with tumour type (p = 0.037) and tumour grade (p = 0.045), but negatively with oestrogen receptor (p = 0.013). It did not correlate with tumour size, axillary lymph node status, progesterone receptor and HER-2 status. MVD varied from 2.09 to 40.38, correlated positively with tumour grade (p = 0.050) and tumour size (p = 0.044), but negatively with progesterone receptor (p = 0.040). MVD did not correlate with tumour type, axillary lymph node status, oestrogen receptor and HER-2. There was no correlation between COX-2 expression and MVD (p = 0.702). CONCLUSIONS: COX-2 expression does not correlate with angiogenesis in breast cancer. Angiogenesis in breast cancer may be dependent on multiple genes, rather than on COX-2 alone. collapse abstract

Comment on "Dynamic response to heat--a novel physical characteristic of breast cancer".

Amplified in breast cancer 1 expression in breast cancer.

AIMS: The amplified in breast cancer 1 (AIB1), steroid receptor co-activator family member, acts as an oestrogen receptor (ER) co-activator. Acting with HER-2, it is thought to play a role in endocrine resistance by facilitating ER-growth factor cros... expand abstractstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. METHODS: A tissue microarray comprising tumours from 438 patients with 15.4 years' median follow-up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. RESULTS: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER-2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. CONCLUSIONS: AIB1 expression correlates with HER-2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER-growth factor interactions. collapse abstract

Revision surgery for breast cancer: single-institution experience.

At Tata Memorial Hospital, as a dedicated breast service at a tertiary cancer center in India, incompletely performed breast surgeries are encountered very frequently; however, there is a lack of published data on incompletely performed breast surger... expand abstracties, revision surgeries, and their outcomes. Between March 2000 and November 2003, the authors audited 850 breast cancer patients who presented at their institute who had undergone surgery outside the institution. On the basis of study criteria, these patients were evaluated for completeness of surgery. Patients in whom the surgical intervention was considered incomplete were evaluated for a completion revision surgery. Of 850 patients, 424 (50%) had undergone surgical intervention with therapeutic intent. Of these 424 patients, 191 (45%) had received incomplete surgical intervention. Completion revision surgery was performed for 153 patients. Complete data were available for 148 patients, of which 123 patients had residual lymph nodes in the axilla. The median number of lymph nodes dissected was 8, and 64 patients had metastatic lymph node(s) left behind. A high proportion of patients with breast cancer who presented at the institute had undergone incomplete surgery outside in nonspecialty centers. Almost half of those patients who underwent incomplete surgery had surgically excisable disease left behind. The possible detrimental impact of inadequate surgical intervention may be very large in India and in other low-resource settings. collapse abstract

What caused the decline in US breast cancer incidence?

Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis.

AIMS: Forkhead box A1 (FOXA1) is a forkhead family transcription factor expressed in breast cancer cells. It is essential for optimal expression of approximately 50% of oestrogen receptor (ER)-related genes. This study explored the FOXA1 relationship... expand abstract with luminal and basal breast cancer subtypes, proliferation markers, and survival in breast cancer patients who had received similar treatment. METHODS: A tissue microarray comprising tumours from 245 invasive breast cancer patients with 67 months of median follow-up was analysed for FOXA1 expression by immunohistochemistry. Interpretable FOXA1 expression, obtained in 184 patients, was analysed along with other variables such as tumour grade, size, nodal status, ER, progesterone receptor, HER2/neu, proliferation and basal markers. RESULTS: FOXA1 expression (score >3) was seen in 139 of 184 breast cancers. It correlated positively with ERalpha (p<0.0001), progesterone receptor (p<0.0001), and luminal subtype (p<0.0001); negatively with basal subtype (p<0.0001), proliferation markers and high histological grade (p = 0.0327). Univariate analysis showed nodal status, tumour grade, ER, progesterone receptor, FOXA1, basal markers and p53 as significant predictors of overall survival. Multivariate analysis showed that only nodal status (p = 0.0006) and ER (p = 0.0017) were significant predictors of OS. In luminal subtype patient subgroup, FOXA1 expression was associated with better survival (p = 0.0284) on univariate analysis. CONCLUSION: Based on this study in patients treated with surgery followed by adjuvant anthracycline-based chemotherapy, FOXA1 expression is associated with good prognosis. It correlates with luminal subtype breast cancer, and could possibly serve as a clinical marker for luminal subtype A. Prognostic ability of FOXA1 in these low-risk breast cancers may prove to be useful in treatment decision making. collapse abstract

Prostanoid receptor EP1 expression in breast cancer.

Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by p... expand abstractrostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P=0.032) and inversely with node positivity (P=0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P=0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression. collapse abstract

FOXA1 expression in breast cancer--correlation with luminal subtype A and survival.

PURPOSE: FOXA1, a forkhead family transcription factor, is essential for optimum expression of approximately 50% of estrogen receptor alpha (ERalpha):estrogen responsive genes. FOXA1 is expressed in breast cancer cells. It segregates with genes that ... expand abstractcharacterize the luminal subtypes in DNA microarray analyses. The utility of FOXA1 as a possible independent prognostic factor has not been determined in breast cancers. MATERIALS AND METHODS: A tissue microarray comprising tumors from 438 patients with 15.4 years median follow-up was analyzed for FOXA1 expression by immunohistochemistry. Interpretable FOXA1 expression obtained in 404 patients was analyzed along with other prognostic factors like tumor grade, size, nodal status, ER, progesterone receptor (PR), and HER2/neu. RESULTS: FOXA1 expression (score >3) was seen in 300 of 404 breast cancers and it correlated with ER (P = 0.000001), PR (P = 0.00001), and luminal A subtype (P = 0.000001). Loss of expression was noted with worsening tumor grade (P = 0.001). Univariate analysis showed nodal status (P = 0.0000012), tumor size (P = 0.00001), FOXA1 (P = 0.0004), and ER (P = 0.012) to be predictors of breast cancer-specific survival. Multivariate analysis showed only nodal status (P = 0.001) and tumor size (P = 0.039) to be significant prognostic factors, whereas FOXA1 (P = 0.060) and ER (P = 0.131) were not significant. In luminal subtype A patient subgroup, FOXA1 expression was associated with better cancer-specific survival (P = 0.024) and in ER-positive subgroup, it was better predictor of cancer-specific survival (P = 0.009) than PR (P = 0.213). CONCLUSION: FOXA1 expression correlates with luminal subtype A breast cancer and it is significant predictor of cancer-specific survival in patients with ER-positive tumors. Prognostic ability of FOXA1 in these low-risk breast cancers may prove to be useful in clinical treatment decisions. collapse abstract

Gene-signature-based prognostic tools in breast cancer: not yet.

Uptake characteristics of FDG in multiple juvenile cellular fibroadenomata of the breast: FDG-PET and histopathologic correlation.

Radiation therapy for ductal carcinoma in situ: is it really worth it?

Tuning into the genetic orchestra using microarrays: limitations of DNA microarrays in clinical practice.

Medical research in India.

Cancer immunotherapeutics: raising the ante.

Developing countries: an evolving opportunity for oncologic research.

Herceptin in early breast cancer: a call for judicious use.

Privately versus publicly managed primary healthcare.

Are there distinct lymphatic flow patterns in the Breast?

Autoantibodies in prostate cancer.

Does primary tumor location have prognostic significance in operable breast cancer?