PIK3CA mutations in breast cancer: A potential predictive marker

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 639-639
Author(s):  
M. Santarpia ◽  
G. Altavilla ◽  
M. Margeli ◽  
M. Mesiti ◽  
V. Cavallari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Detection System ◽  
Progesterone Receptors ◽  
Predictive Marker ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Sequence Detection ◽  
Pik3ca Mutations

639 Background: Somatic mutations in phosphoinositide-3-kinase catalytic alpha (PIK3CA) activates Akt, attenuates apoptosis and promotes tumor invasion. The common mutations E545K and H1047R confer resistance to paclitaxel in immortalized breast cancer cell lines. We screened primary breast cancers for PIK3CA mutations in the helical and catalytic domains. Methods: Tumor samples from 61 stage I-III breast cancer patients treated with adjuvant chemo- and/or hormone therapy were examined for PIK3CA mutations E542K, E545K and H1047R by the 5-nuclease assay (TaqMan) using the ABI Prism 7900HT Sequence Detection System. Results: Mutations were found in 17 patients (27.9%): 6 E542K; 5 E545K; 6 H1047R. PIK3CA mutations were not associated with expression of estrogen or progesterone receptors, lymph node metastases, or ERBB2 overexpression. (See table ) Conclusions: PIK3CA mutations occur frequently in breast cancer and could be a novel predictive marker of chemoresistance and an appealing target for therapeutic inhibition, independent of hormone receptors and ERBB2 status. [Table: see text] No significant financial relationships to disclose.

Expression of hormone receptors ERα, ERβ and PgR in HER2-positive breast cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10525-10525
Author(s):  
M. Litwiniuk ◽  
V. Filas ◽  
J. Moczko ◽  
R. Kaleta ◽  
J. Breborowicz
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Detection System ◽  
Statistical Significance ◽  
Her2 Status ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

10525 Background: HER-2/neu gene is amplified and overexpressed in 15–20% of invasive breast cancers. HER2-positive breast cancers have a worse prognosis than HER2-negative tumors and distinctive clinical features. They express hormone receptors for estrogen (ERα) and for progesterone (PgR) less frequently than HER2-negative tumors. The identification of the other human estrogen receptor, receptor beta (ERβ), raises a question of ERβ occurrence in HER2-positive breast cancer. Patients and methods: Formalin-fixed, paraffin embedded tissues from 90 patients with invasive HER2-positive breast cancer and from 99 patients with HER2-negative breast cancer were used in this study. The HER2 status was analyzed using HercepTest TM (IHC), and IHC 2+ results were confirmed with FISH test. Immunostaining for ERα, ERβ and PgR was performed using monoclonal antibodies against ERα, PgR (DakoCytomation) and against ERβ (CHEMICON). The EnVision detection system was applied. The data were analyzed using nonparametric Fisher-Freeman-Halton test; the statistical significance was considered when p < 0.5. Results: Only 33% of the HER2-positive breast cancers were ERα-positive compared with 63% in the HER2-negative group (p < 0.001). The expression of ERβ protein was observed in almost equal frequency in both groups (57% of HER2-positive breast cancers and 57.7% of HER2-negative tumors, p = 0.889). The expression of PgR was observed in 30% of HER2-positive breast cancers and in 68.7% of HER2-negative tumors (p < 0.001). Conclusion: The expression of ERβ (unlike that of ERα and PgR) was similar in HER2-positive and in HER2-negative breast cancers. Thus, ERβ may be a potential target in future endocrine therapy for women with HER2-positive breast cancers. No significant financial relationships to disclose.

scholarly journals A High-Content Assay to Identify Small-Molecule Modulators of a Cancer Stem Cell Population in Luminal Breast Cancer

2012 ◽  
Vol 17 (9) ◽  
pp. 1211-1220 ◽  
Author(s):  
Byong Hoon Yoo ◽  
Sunshine Daddario Axlund ◽  
Peter Kabos ◽  
Brian G. Reid ◽  
Jerome Schaack ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Population ◽  
Hormone Receptors ◽  
Fluorescent Protein ◽  
Breast Cancer Incidence ◽  
Stem Cell Population ◽  
Breast Cancer Cell Lines ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Green Fluorescent

Breast cancers expressing hormone receptors for estrogen (ER) and progesterone (PR) represent ~70% of all cases and are treated with both ER-targeted and chemotherapies, with near 40% becoming resistant. We have previously described that in some ER+ tumors, the resistant cells express cytokeratin 5 (CK5), a putative marker of breast stem and progenitor cells. CK5+ cells have lost expression of ER and PR, express the tumor-initiating cell surface marker CD44, and are relatively quiescent. In addition, progestins, which increase breast cancer incidence, expand the CK5+ subpopulation in ER+PR+ breast cancer cell lines. We have developed models to induce and quantitate CK5+ER−PR− cells, using CK5 promoter-driven luciferase (Fluc) or green fluorescent protein (GFP) reporters stably transduced into T47D breast cancer cells (CK5Pro-GFP or CK5Pro-Luc). We validated the CK5Pro-GFP-T47D model for high-content screening in 96-well microplates and performed a pilot screen using a focused library of 280 compounds from the National Institutes of Health clinical collection. Four hits were obtained that significantly abrogated the progestin-induced CK5+ cell population, three of which were members of the retinoid family. Hence, this approach will be useful in discovering small molecules that could potentially be developed as combination therapies, preventing the acquisition of a drug-resistant subpopulation.

Stage at breast cancer diagnosis is more advanced in BRCA1 carriers but not in BRCA2 carriers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10540-10540
Author(s):  
B. Kaufman ◽  
A. Lahad ◽  
M. Krieger ◽  
M. Gal ◽  
E. Friedman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Medullary Carcinoma ◽  
Breast Cancer Diagnosis ◽  
Age At Diagnosis ◽  
Stage At Diagnosis ◽  
Breast Cancers ◽  
Pathological Features ◽  
Breast Cancer Patients ◽  
Brca1 Carriers

10540 Background: BRCA1-associated tumors are known to have less favorable pathological characteristics, but there is little information on whether this is also reflected in the stage at diagnosis. Methods: Clinical and pathological information was collected on 1,122 consecutive Ashkenazi Jewish breast cancer patients who were tested post-diagnosis for the BRCA1/2 mutations common in this population. Results: Of 1,122 patients, 70 (6.2%) were BRCA1 and 50 (4.5%) were BRCA2 carriers. Mean age at diagnosis was 49.9 yrs. in BRCA1 carriers (p=.0001 vs. non-carriers (NC)) vs. 52.0 yrs. in BRCA2 carriers (p=.02 vs. NC) and 56.0 yrs. in NC. Pure DCIS was less common in BRCA1 carriers (3%) than in BRCA2 carriers (8.2%) and NC (11.8%) (p=.03). Medullary carcinoma was more common in BRCA1 (9.8%) and BRCA2 carriers (6.7%) than in NC (1.5%) (p<.001). Invasive lobular carcinomas were rarer in BRCA1 (1.6%) and BRCA2 (2.2%) compared to NC (8.8%) (p=.012). Hormone receptors (HR) negative was more common in BRCA1 (62%) compared to BRCA2 carriers (21%) (p=.00006) and NC (17%) (p<0.0001). Triple negative tumors (HR and HER2 negative) were more common in BRCA1 carriers (60%) than in BRCA2 carriers (14%) and NC (8.3%) (p=0.001). High grade was more common in BRCA1 (60.4%) and BRCA2 (51.4%) carriers than in NC (36.7%, p=.001). Less favorable pathological features and younger age at diagnosis in BRCA1 carriers were reflected in a more advanced stage at diagnosis. Stage I at diagnosis was found in 34% of BRCA1 carriers (p=.05 vs. NC), 43% of BRCA2 carriers and 46% of NC, stage II in 48% of BRCA1 carriers, 41% of BRCA2 carriers and 37% of NC, and stage III in 17% of BRCA1 carriers, 13.5% of BRCA2 carriers and 13.5% of non-carriers. Conclusions: This consecutive cohort study demonstrates that breast cancers in BRCA1 carriers are characterized by more aggressive pathological features and are diagnosed at more advanced stages than in BRCA2 carriers and non-carriers. This may suggest a differential approach for prevention and surveillance in BRCA1 compared to BRCA2 carriers. No significant financial relationships to disclose.

scholarly journals Immunohistochemical Targeting of p110β Isoform of phosphatidylinositol 3-kinase co-associated with Cyclin-Dependent Kinase 1 in a Group of Tissues from Iraqi Patients with Breast Cancer

2019 ◽  
Vol 13 (2) ◽  
pp. 127-136
Author(s):  
Mohammed A.M. Al-Qurtas
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Detection System ◽  
Breast Tumors ◽  
Normal Breast ◽  
Control Group ◽  
P Value ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Benign Breast Tumors

Background: While two-thirds of breast cancers express hormone receptors for either estrogen (ER) and/or progesterone (PR) , genetically altered PI3K pathway was found in more than 70% of ER-positive breast cancers.An aberrant activity of cyclin-dependent kinase 1 (CDK1) in a wide variety of human cancers has selectively constituted an attractive pharmacological targets in MYC-dependent human breast cancer cells. Aim of the study:  Role of p110-beta as well as and CDK 1  in the pathogenesis of subset of breast cancers and contribution in their carcinogenesis. Type of the study: is a retrospective study Methods: This retrospective research enrolled 70 paraffin embedded breast tissue blocks which were retrieved from archives of the period 2011 till 2017 at major hospitals and private histopathological laboratories as well as Forensic Medicine Institute in Baghdad. They comprised 30 breast cancers, 25 benign breast tumors and 15 apparently normal breast autopsies. Two 4 mm - thick sections were specified on positively charged slides for monoclonal primary p110 as well as and CDK 2 antibodies using immune-enzymatic antigen detection system for immunohistochemistry (IHC) techniques. Results: Seventeen out of 30 (56.7%) of the total breast cancer cases in this study showed positive immunohistochemistry reaction(IHC) for detection of P110- beta gene expression in these tissues.  In the benign group, 6 out of 25 cases (24%) revealed positive IHC signals. None of control group presented positive signals. The differences begroup tween the percentages of P110-beta in breast cancers and each of control group and benign breast tumors group are statistically very highly significant (P value = < 0.0001). The expression of CDK1 was detected in 53.3% (16 out of 30) of breast cancers tissues and in 44% (11 out of 25) benign breast tumors, whereas none of control group of tissues showed CDK1- expression. Conclusions: The present data indicate that p110-beta as well as and CDK 1 could have a role in the pathogenesis of subset of breast cancers and contribution in their carcinogenesis.

scholarly journals Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

2021 ◽  
pp. 153537022199109
Author(s):  
Stephanie Colón-Marrero ◽  
Shirley Jusino ◽  
Yainyrette Rivera-Rivera ◽  
Harold I Saavedra
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Hormone Receptors ◽  
Chromosome Instability ◽  
Therapeutic Interventions ◽  
Breast Cancers ◽  
Biological Therapies ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Mitotic Kinases

Biological therapies against breast cancer patients with tumors positive for the estrogen and progesterone hormone receptors and Her2 amplification have greatly improved their survival. However, to date, there are no effective biological therapies against breast cancers that lack these three receptors or triple-negative breast cancers (TNBC). TNBC correlates with poor survival, in part because they relapse following chemo- and radio-therapies. TNBC is intrinsically aggressive since they have high mitotic indexes and tend to metastasize to the central nervous system. TNBCs are more likely to display centrosome amplification, an abnormal phenotype that results in defective mitotic spindles and abnormal cytokinesis, which culminate in aneuploidy and chromosome instability (known causes of tumor initiation and chemo-resistance). Besides their known role in cell cycle control, mitotic kinases have been also studied in different types of cancer including breast, especially in the context of epithelial-to-mesenchymal transition (EMT). EMT is a cellular process characterized by the loss of cell polarity, reorganization of the cytoskeleton, and signaling reprogramming (upregulation of mesenchymal genes and downregulation of epithelial genes). Previously, we and others have shown the effects of mitotic kinases like Nek2 and Mps1 (TTK) on EMT. In this review, we focus on Aurora A, Aurora B, Bub1, and highly expressed in cancer (Hec1) as novel targets for therapeutic interventions in breast cancer and their effects on EMT. We highlight the established relationships and interactions of these and other mitotic kinases, clinical trial studies involving mitotic kinases, and the importance that represents to develop drugs against these proteins as potential targets in the primary care therapy for TNBC.

scholarly journals Study of ER PR receptors in breast carcinoma: a study of 30 cases

2018 ◽  
Vol 5 (11) ◽  
pp. 3738
Author(s):  
Himanshu R. Patel ◽  
Ankur Shrimal ◽  
Harsh P. Trivedi
Keyword(s):  
Breast Cancer ◽  
Retrospective Study ◽  
Breast Carcinoma ◽  
Hormone Receptors ◽  
Tertiary Care ◽  
Progesterone Receptors ◽  
Care Hospital ◽  
Breast Cancer Patients ◽  
Estrogen And Progesterone Receptors ◽  
Medical College

Background: Estrogen and Progesterone receptors are found in breast cancer cells that depend on estrogen and related hormones to grow. These are steroidal nuclear type of receptors. The most common method currently used to test a tumor for estrogen and progesterone receptors is immunohistochemistry or IHC. Patients with positive hormone receptor cancer have better survival. They are candidates of anti-hormonal therapy.Methods: This is a retrospective study was carried out in the Department of Surgery of a tertiary care hospital, affiliated to Government Medical College. This is a retrospective study in which 30 randomly selected case records of breast cancer patients, who presented in the period between 2011 to 2016, and who had undergone surgery, were taken and studied in terms of history, examination, investigations, treatment given, histopathology report and development of recurrence, metastasis and survival.Results: In this study out of 30 patients, 25 patients received adjuvant chemotherapy. 2 patients developed recurrence at local site.1 patient was ER/PR both negative and 1 patient was ER +/PR-. 3 patients developed metastasis. Among these, 2 patients were ER/PR both negative and 1 patient was having ER/PR both positive.Conclusions: Hormone receptors play a significant role in breast carcinoma. Breast cancer is more common in postmenopausal group as compared to premenopausal group. Mean age at diagnosis of breast cancer in western countries is 61 years and in India it is 50 years.

scholarly journals Minireview: Nuclear Receptors and Breast Cancer

2008 ◽  
Vol 22 (10) ◽  
pp. 2215-2228 ◽  
Author(s):  
Suzanne D. Conzen
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cell ◽  
Signaling Pathways ◽  
Cancer Biology ◽  
Progesterone Receptors ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Breast Cancer Patients

Abstract Until recently, the study of nuclear receptor (NR) function in breast cancer biology has been largely limited to estrogen and progesterone receptors. The development of reliable gene expression arrays, real-time quantitative RT-PCR, and immunohistochemical techniques for studying NR superfamily members in primary human breast cancers has now revealed the presence and potential importance of several additional NRs in the biology of breast cancer. These include receptors for steroid hormones (including androgens and corticosteroids), fat-soluble vitamins A and D, fatty acids, and xenobiotic lipids derived from diet. It is now clear that after NR activation, both genomic and nongenomic NR pathways can coordinately activate growth factor signaling pathways. Advances in our understanding of both NR functional networks and epithelial cell growth factor signaling pathways have revealed a frequent interplay between NR and epithelial cell growth factor family signaling that is clinically relevant to breast cancer. Understanding how growth factor receptors and their downstream kinases are activated by NRs (and vice-versa) is a central goal for maximizing treatment opportunities in breast cancer. In addition to the estrogen receptor, it is predicted that modulating the activity of other NRs will soon provide novel prevention and treatment approaches for breast cancer patients.

scholarly journals 90 YEARS OF PROGESTERONE: Progesterone and progesterone receptors in breast cancer: past, present, future

2020 ◽  
Vol 65 (1) ◽  
pp. T49-T63 ◽  
Author(s):  
Kathryn B Horwitz ◽  
Carol A Sartorius
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Incidence ◽  
Progesterone Receptors ◽  
Predictive Marker ◽  
Breast Cancers ◽  
Physiological Processes ◽  
History Of ◽  
Bona Fide ◽  
Treatment Responses

Progesterone and progesterone receptors (PR) have a storied albeit controversial history in breast cancers. As endocrine therapies for breast cancer progressed through the twentieth century from oophorectomy to antiestrogens, it was recognized in the 1970s that the presence of estrogen receptors (ER) alone could not efficiently predict treatment responses. PR, an estrogen regulated protein, became the first prognostic and predictive marker of response to endocrine therapies. It remains today as the gold standard for predicting the existence of functional, targetable ER in breast malignancies. PRs were subsequently identified as highly structured transcription factors that regulate diverse physiological processes in breast cancer cells. In the early 2000s, the somewhat surprising finding that prolonged use of synthetic progestin-containing menopausal hormone therapies was associated with increased breast cancer incidence raised new questions about the role of PR in ‘tumorigenesis’. Most recently, PR have been linked to expansion of cancer stem cells that are postulated to be the principal cells reactivated in occult or dormant disease. Other studies establish PR as dominant modulators of ER activity. Together, these findings mark PR as bona fide targets for progestin or antiprogestin therapies, yet their diverse actions have confounded that use. Here we summarize the early history of PR in breast cancer; debunk the theory that progesterone causes cancer; discuss recent discoveries that PR regulate cell heterogeneity; attempt to unify theories describing PR as either good or bad actors in tumors; and discuss emerging areas of research that may help explain this enigmatic hormone and receptor.

scholarly journals WNK1 Enhances Migration and Invasion in Breast Cancer Models

2021 ◽  
Author(s):  
Ankita B. Jaykumar ◽  
Jiung Jung ◽  
Pravat Parida ◽  
Tuyen T. Dang ◽  
Magdalena Grzemska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Collagen Matrices ◽  
Cancer Models ◽  
Protein Components

AbstractMetastasis is the major cause of mortality in breast cancer patients. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase WNK1 (with no lysine (K) 1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.

Human kallikrein 10, a predictive marker for breast cancer

2006 ◽  
Vol 387 (6) ◽  
pp. 715-721 ◽  
Author(s):  
Ying Zhang ◽  
Ishfaq Bhat ◽  
Musheng Zeng ◽  
Goyal Jayal ◽  
David E. Wazer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ductal Carcinoma ◽  
Mammary Epithelial Cells ◽  
Predictive Marker ◽  
Normal Breast ◽  
Mammary Epithelial ◽  
Lymphocytic Leukemia ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Specific Pcr

AbstractOur laboratory is involved in identifying genes that can be used as early diagnostic or prognostic markers in breast cancer. We previously identified a gene (NES1) that is expressed in normal but not in transformed mammary epithelial cells (MECs).NES1is located on chromosome 19q13.4 within the kallikrein locus and thus was designated as human kallikrein 10 (hK10), although we have been unable to detect any protease activity. Importantly,hK10expression is decreased in a majority of breast cancer cell lines. Transfection ofhK10intohK10-negative breast cancer cells reduces the tumorigenicity. Using methylation-specific PCR and subsequent sequencing, we demonstrate a strong correlation between hypermethylation ofhK10and loss of mRNA expression. Further analysis showed that essentially 100% of normal breast specimens hadhK10expression, whereas 46% of ductal carcinomain situ(DCIS) and the majority of infiltrating ductal carcinoma (IDC) samples lacked thehK10 mRNA. Importantly,hK10-negative DCIS diagnosed at the time of biopsy were subsequently diagnosed as IDC at the time of definitive surgery. It has been shown that hK10 protein expression is regulated by steroids. In addition to breast cancers, hK10 is downregulated in cervical cancer, prostate cancer and acute lymphocytic leukemia, whereas it is upregulated in ovarian cancers. These results point to the paradoxical role of hK10 in human cancers and underscore the importance of further studies of this kallikrein.

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