Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression are crucial in the biology of breast carcinoma. HER-2/neu gene is amplified and overexpressed in 15-30% of invasive breast cancers. HER-2-positive breast cancers have worse prognosis than HER-2 negative tumors and possess distinctive clinical features. The aim of this study was to assess the expression of HER2 in cancer tissue of patients with invasive breast cancer in correlation with tumor type, histological grade, tumor size, lymph node status, and expression of estrogen receptor and progesterone receptor.
Material and methods
Formalin-fixed, paraffin-embedded tissues from 40 patients with invasive HER-2-positive breast cancer and from 191 patients with HER-2-negative breast cancer were used in this study. HER2 expression was determined using the test HerceptTest™ DAKO.
Among 231 cases of breast cancer, 18 invasive lobular carcinomas and 213 invasive ductal carcinomas were diagnosed. Sixty percent of HER-2-positive breast cancers were ER-positive compared with 77% in the HER-2-negative group (p = 0.002). The expression of PR was observed in 43% of HER-2-positive breast cancers and in 72% of HER2-negative tumors (p = 0.003). Excessive expression of HER2 protein was detected in 60% of patients positive for estrogen receptors, which may worsen prognosis in these patients.
Determination of HER2 overexpression in breast cancer patients, allows for a determination of a group of patients with a worse prognosis.
invasive ductal carcinoma; invasive lobular carcinoma; human epidermal growth factor receptor 2; estrogen receptor; progesterone receptor
Sex differences exist in the site specific incidences of colorectal cancer. The increased incidence of colonic cancer in women with breast cancer and the protective effect of increasing parity suggest a role for sex hormones. To explore the molecular basis, the expression of messenger RNA for oestrogen and progesterone receptors in the large bowel has been studied. With northern and dot blot analyses mRNA coding for oestrogen receptor and progesterone receptor in large bowel cancers and corresponding normal mucosa and in adenomatous polyps has been identified. There were no significant differences in receptor mRNA concentrations between males and females or between cancers, normal mucosae, and polyps, except for rectal cancers, which had higher progesterone receptor concentrations than corresponding normal tissue. Oestrogen and progesterone receptor mRNA concentrations were strongly correlated in both cancers and normal tissues. Enzyme immunoassay for oestrogen receptor gave values of 1.2-7.4 fmol/mg total protein, an amount similar to that seen in normal breast tissue. Oestrogen receptor protein and mRNA for oestrogen receptor and progesterone receptor are present in the large bowel.
Estrogen and progesterone are the defining hormones of normal female development, and both play critical roles in breast carcinogenesis. Cyclin D1 is a breast cancer oncogene whose amplification is linked to poor prognosis in estrogen and progesterone receptor-positive breast cancers. Here we report that cyclin D1 regulates progesterone receptor expression, consequently enhancing responses to estrogen and progesterone. Estrogen treatment of cyclin D1 transgenic mice increased progesterone receptor expression and induced mammary hyperplasias that were stimulated by progesterone and blocked by a progesterone antagonist. Progesterone receptor levels decreased in cyclin D1 knockout mice. Cyclin D1 regulated progesterone receptor expression through a novel estrogen- and cyclin D1-responsive enhancer in DNA encoding part of the 3′ untranslated region of the progesterone receptor gene. Small inhibitory RNAs for cyclin D1 decreased progesterone receptor expression and estrogen receptor binding to the 3′ enhancer region in human breast cancer cells. Since estrogen and progesterone regulate cyclin D1, our results suggest that cyclin D1's participation in a feed-forward loop could contribute to increased breast cancer risks associated with estrogen and progesterone combinations. Additionally, its regulation of the progesterone receptor identifies a novel role for cyclin D1 in ovarian hormone control of breast development and breast carcinogenesis.
To correlate high resolution dynamic MR features with prognostic factors in breast cancer.
Materials and Methods
One hundred and ninety-four women with invasive ductal carcinomas underwent dynamic MR imaging using T1-weighted three-dimensional fast low-angle shot (3D-FLASH) sequence within two weeks prior to surgery. Morphological and kinetic MR features were determined based on the breast imaging and reporting data system (BI-RADS) MR imaging lexicon. Histological specimens were analyzed for tumor size, axillary lymph node status, histological grade, expression of estrogen receptor (ER), expression of progesterone receptor (PR), and expression of p53, c-erbB-2, and Ki-67. Correlations between the MR features and prognostic factors were determined using the Pearson χ2 test, linear-by-linear association, and logistic regression analysis.
By multivariate analysis, a spiculated margin was a significant, independent predictor of a lower histological grade (p < 0.001), and lower expression of Ki-67 (p = 0.007). Rim enhancement was significant, independent predictor of a higher histological grade (p < 0.001), negative expression of ER (p = 0.001), negative expression of PR (p < 0.001) and a larger tumor size (p = 0.006). A washout curve may predict a higher level of Ki-67 (p = 0.05). Most of the parameters of the initial enhancement phase cannot predict the status of the prognostic factors. Only the enhancement ratio may predict a larger tumor size (p = 0.05).
Of the BI-RADS-MR features, a spiculated margin may predict favorable prognosis, whereas rim enhancement or washout may predict unfavorable prognosis of breast cancer.
Breast neoplasms; Breast, MR; Prognostic factors
It has been reported that the sodium/iodide symporter (NIS) gene is expressed in several breast cancer tissues, suggesting the possibility of radionuclide imaging and therapy. However, the regulatory mechanism of NIS gene expression in breast cancer is not yet understood. To assess the relationship between the hormonal status and the NIS expression in breast cancer tissue, we investigated the NIS expression and correlated it to the expression of the thyrotropin receptor (thyroid stimulating hormone receptor, TSH-R), the estrogen receptor (ER) and the progesterone receptor (PR) in human breast cancer tissues.
Materials and Methods
Breast cancer tissues were obtained from 44 patients. Pathological examination showed 2 cases of Grade I, 17 of Grade II, 22 of Grade III, and 3 of unknown grade. We measured the expression of NIS and TSH-R genes by using RT-PCR and we measured the status of ER and PR by using immunohistochemistry.
The NIS gene was expressed in 15 (34%) of the 44 breast cancer tissues. The NIS gene was expressed in 32% of the cases with TSH-R gene expression. The NIS gene was expressed in 40% of the breast cancer tissues with a positive PR and in 31% with a negative PR (p>0.05). It was positive for PR in 18% of the cases and negative for PR in 39% of the cases (p>0.05).
The NIS gene is expressed in approximately one-third of the human breast cancer tissues. Its expression was not related to the presence of the TSH-R gene or hormonal receptors, ER and PR.
Breast neoplasms; Estrogen receptors; Progesterone receptors; Sodium/iodide symporter; Thyrotropin receptors
Distant metastasis and recurrence are major prognostic factors associated with breast cancer. Both lymphovascular invasion (LVI) and blood vessel invasion (BVI) are important routes for metastasis to regional lymph nodes and for systemic metastasis. Despite the importance of vascular invasion as a prognostic factor, application of vascular invasion as a histopathological criterion is controversial. The aim of this study was to distinguish LVI from BVI in prognosis and recurrence of breast cancer using an endothelial subtype specific immunohistochemical stain (podoplanin, D2-40, and CD31).
Sections from 80 paraffin-embedded archival specimens of invasive breast cancer were stained for podoplanin, D2-40, or CD31 expression. Immunohistochemical staining results were correlated with clinicopathological features, such as tumor size, status of lymph node metastases, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor-2 expression, and recurrence. Patients with ductal carcinoma in situ and stage IV breast cancer were excluded.
A significant correlation was found between D2-40 LVI positivity and lymph node metastasis (p=0.022). We found a significant correlation between D2-40 LVI positivity and recurrence of breast cancer (p=0.014). However, no significant correlation was found between BVI and recurrence. A poorer disease free survival was shown for D2-40 positive LVI (p=0.003). In a multivariate analysis, the presence of D2-40 LVI positivity revealed a significant association with decreased disease-free survival.
D2-40 LVI positivity was a more prognostic predictor of breast cancer than BVI.
Breast cancer; CD31 antigen; Monoclonal antibody D2-40; Prognosis; Survival
To investigate possible relationships between genetic alterations and hormonal deregulation during breast cancer development and/or progression, we examined 616 primary breast cancers for loss of heterozygosity (LOH) at chromosomal regions 16q24, 17p13.3 and 17q21, and for amplifications of the ERBB2 and c-MYC loci. A comparison of oestrogen receptor (ER) and progesterone receptor (PgR) status in tumour cells with data concerning these genetic alterations revealed that LOH at 17q21 was significantly correlated with absence of oestrogen receptors (ER) (P < 0.0003) or progesterone receptors (PgR) (P < 0.0001), and with the absence of both (P < 0.0001). Similarly, a significant association was observed between amplification of ERBB2 and the absence of either ER or PgR. LOH at 17p13.3 was associated with the absence of PgR (P < 0.01). These data suggest a possible relationship between specific genetic changes on chromosome 17 and hormonal deregulation in the progression of breast cancer.
Aurora A kinase, a centrosomal serine/threonine kinase which plays an essential role in chromosome segregation during cell division, is commonly amplified and/or over expressed in human malignancies. Aurora A is suggested to be one of the proliferation parameters which is an independent prognostic factor for early invasive breast cancer patients; however the individual clinical or prognostic relevance of this gene has been a matter of debate.
A comprehensive analysis of Aurora A at the levels of gene expression, gene copy number and protein expression was performed for 278 primary invasive breast cancer patients; and the correlation with clinical outcomes were investigated.
Aurora A gene expression level not only correlated with gene amplification, but was also significantly associated with several clinicopathological parameters and patient prognosis. Patients with higher nuclear grade, negative progesterone receptor status and higher Ki67 expressed higher levels of Aurora A mRNA, which was associated not only with poor relapse-free survival (RFS) but was also found to be a significant multivariate parameter for RFS. Aurora A protein expression was also significantly associated with clinicopathological characteristics; lymph node status, nuclear grade, estrogen receptor status and Ki67, but not with prognosis. By contrast, Aurora A gene amplification correlated with tumor size, nuclear grade and Ki67, and had no prognostic value.
Our data indicate that Aurora A gene expression is an effective tool, which defines both tumor proliferation potency and patient prognosis.
Aurora A; Breast cancer; Biomarker; Transcript levels
Estrogen and progesterone hormones are key regulators of a wide variety of biological processes. In addition to their influence on reproduction, cell differentiation and apoptosis, they affect inflammatory response, cell metabolism and most importantly, they regulate physiological breast tissue proliferation and differentiation as well as the development and progression of breast cancer. In order to assess whether genetic variants in the steroid hormone receptor gene ESR1 (estrogen receptor alpha) had an effect on sporadic breast cancer susceptibility, we assessed 7 ESR1 single nucleotide polymorphisms (SNPs) for associations with breast cancer susceptibility and clinical parameters in 221 breast cancer patients and 221 controls, respectively. We identified ESR1 intron SNP +2464 C/T (rs3020314) and ESR1 intron SNP -4576 A/C (rs1514348) to correlate with breast cancer susceptibility and progesterone receptor expression status. Patients genotyped CT for ESR1 intron SNP +2464 (rs3020314) (p ≤ 0.045) or genotyped AC for ESR1 intron SNP -4576 (rs1514348) (p ≤ 0.000026) were identified to carry a significant risk as to the development of breast cancer in the Central European Caucasian population (both together: p ≤ 0.000488). Our study could confirm previous associations and revealed new associations of SNP rs1514348 with susceptibility to breast cancer and clinical outcome, which might be used as new additional SNP markers.
Estrogen receptor; ESR1; SNP; breast cancer
Expression of estrogen and progesterone hormone receptors indicates a favorable prognosis due to the successful use of hormonal therapies such as tamoxifen and aromatase inhibitors. Unfortunately, 15–20% of patients will experience breast cancer recurrence despite continued use of tamoxifen. Drug resistance to hormonal therapies is of great clinical concern so it is imperative to identify novel molecular factors that contribute to tumorigenesis in hormone receptor positive cancers and/or mediate drug sensitivity. The hope is that targeted therapies, in combination with hormonal therapies, will improve survival and prevent recurrence. We have previously shown that the DEK oncogene, which is a chromatin remodeling protein, supports breast cancer cell proliferation, invasion and the maintenance of the breast cancer stem cell population. In this report, we demonstrate that DEK expression is associated with positive hormone receptor status in primary breast cancers and is up-regulated in vitro following exposure to the hormones estrogen, progesterone, and androgen. Chromatin immunoprecipitation experiments identify DEK as a novel estrogen receptor α (ERα) target gene whose expression promotes estrogen-induced proliferation. Finally, we report for the first time that DEK depletion enhances tamoxifen-induced cell death in ER+ breast cancer cell lines. Together, our data suggest that DEK promotes the pathogenesis of ER+ breast cancer and that the targeted inhibition of DEK may enhance the efficacy of conventional hormone therapies.
The objective of this study was to determine the concordance rate between core needle biopsy (CNB) and surgical excision of invasive breast cancer regarding the oestrogen receptor (ER) and Progesterone receptor (PgR) status as determined by Immunohistochemistry (IHC).
Hormone receptor status was established using IHC (using quickscore system 0–8) on preoperative CNB and subsequent surgical excision in 93 patients with invasive breast cancer. Results were compared taking into account tumour's size, grade, and patient's age.
The ER concordance rate between CNB and surgical excisions was 95%. The PgR concordance rate was 89%. This shows that CNB has a sensitivity of 97% for ER and 95% for PgR.
There is a positive correlation of ER and PgR between CNB and surgical excision (p < 0.000001). There was no significant difference in the number of core biopsies between concordant and discordant cases.
Preoperative core biopsy is highly sensitive for the IHC detection of ER and PgR in invasive breast cancer. The concordance rate is higher for ER than PgR, which could be due to the fact that ER is more homogeneously distributed.
core needle biopsy; oestrogen receptors; progesterone receptors
Background and Purpose: Triple Negative Breast Cancer (TNBC) is defined by a lack of expression of the steroid hormone receptors (oestrogen and progesterone), and the human epidermal growth factor receptor-2 (HER-2). It is characterized by distinct molecular, histological and clinical features. It is a high risk breast cancer that lacks the benefit of a specific therapy.
Our study was aimed at pathologically illustrating triple-negative breast carcinoma and at evaluating the expression of the Epidermal Growth Factor Receptor (EGFR) ,cytokeratin 5/6 (CK 5/6) and Ki-67 among triple-negative breast cancer cases. Further, we aimed to probe whether triple–negative phenotype could be a surrogate marker for the basal phenotype and to correlate the expression of the basal markers (CK 5/6 and EGFR) with the clinico-pathological prognostic parameters.
Methods: The expression of EGFR, CK 5/6 and Ki-67 were studied by immunohistochemistry (IHC) in 50 triple-negative breast cancer cases.
Statistical Analysis: A statistical analysis was implemented by using the SPSS version 20.0. The Chi-square test was conducted to assess the relationship between the immunohistochemical markers and other variables. The Fischer exact test was used when the expected cell counts were less than 5.
Results: The women with triple-negative breast cancer were younger, with the adverse pathological characteristics of a high tumour grade, tumour necrosis, frequent nodal metastases and high proliferation. 37 (74%) of the 50 triple-negative breast carcinomas showed the expression of the basal markers (EGFR and /or CK 5/6). We observed a statistically significant association between the basal marker expression and the presence of tumour necrosis.
Conclusion: The triple-negative breast cancers in our population harbour adverse pathobiological features and a five marker immunohistochemical panel can be reliably used to define the basal-like cancers. The “Triple-negative” status cannot be used as a surrogate for the “basal marker expression”.
Breast cancer; Triple-negative; Basal-like; EGFR; CK 5/6
Progesterone receptor status is a marker for hormone responsiveness and disease prognosis in breast cancer. Progesterone receptor negative tumours have generally been shown to have a poorer prognosis than progesterone receptor positive tumours. The observed loss of progesterone receptor could be through a range of mechanisms, including the generation of alternatively spliced progesterone receptor variants that are not detectable by current screening methods. Many progesterone receptor mRNA variants have been described with deletions of various whole, multiple or partial exons that encode differing protein functional domains. These variants may alter the progestin responsiveness of a tissue and contribute to the abnormal growth associated with breast cancer. Absence of specific functional domains from these spliced variants may also make them undetectable or indistinguishable from full length progesterone receptor by conventional antibodies. A comprehensive investigation into the expression profile and activity of progesterone receptor spliced variants in breast cancer is required to advance our understanding of tumour hormone receptor status. This, in turn, may aid the development of new biomarkers of disease prognosis and improve adjuvant treatment decisions.
Loss of hormone receptor (HR) status in breast carcinomas is associated with increased tumour cell motility and invasiveness. In an immunohistological study of 58 primary breast cancers, oestrogen (ER) and progesterone (PR) receptor levels were inversely correlated with the expression of fascin, an actin-bundling protein associated with cell motility (P< 0.0001 and P = 0.0019, respectively). In addition, fascin was preferentially expressed in non-diploid tumours (P = 0.03). In summary, the upregulation of fascin in HR-negative breast cancers may contribute to their more aggressive behaviour. © 2000 Cancer Research Campaign
fascin; breast cancer; motility; hormone receptor oestrogen; progesterone
Medroxyprogesterone acetate (MPA), the major progestin used for oral contraception and hormone replacement therapy, has been implicated in increased breast cancer risk. Is this risk due to its progestational or androgenic properties? To address this, we assessed the transcriptional effects of MPA as compared with those of progesterone and dihydrotestosterone (DHT) in human breast cancer cells.
A new progesterone receptor-negative, androgen receptor-positive human breast cancer cell line, designated Y-AR, was engineered and characterized. Transcription assays using a synthetic promoter/reporter construct, as well as endogenous gene expression profiling comparing progesterone, MPA and DHT, were performed in cells either lacking or containing progesterone receptor and/or androgen receptor.
In progesterone receptor-positive cells, MPA was found to be an effective progestin through both progesterone receptor isoforms in transient transcription assays. Interestingly, DHT signaled through progesterone receptor type B. Expression profiling of endogenous progesterone receptor-regulated genes comparing progesterone and MPA suggested that although MPA may be a somewhat more potent progestin than progesterone, it is qualitatively similar to progesterone. To address effects of MPA through androgen receptor, expression profiling was performed comparing progesterone, MPA and DHT using Y-AR cells. These studies showed extensive gene regulatory overlap between DHT and MPA through androgen receptor and none with progesterone. Interestingly, there was no difference between pharmacological MPA and physiological MPA, suggesting that high-dose therapeutic MPA may be superfluous.
Our comparison of the gene regulatory profiles of MPA and progesterone suggests that, for physiologic hormone replacement therapy, the actions of MPA do not mimic those of endogenous progesterone alone. Clinically, the complex pharmacology of MPA not only influences its side-effect profile; but it is also possible that the increased breast cancer risk and/or the therapeutic efficacy of MPA in cancer treatment is in part mediated by androgen receptor.
The validity of determining the progesterone receptor status of breast carcinomas with a monoclonal antibody was investigated by comparison with data from a radioligand binding assay on adjacent cryostat sections of 103 tumours. Significant nuclear staining for progesterone receptor was observed in 37 (36%) of the tumours studied and this showed a close correlation with the results of radioligand binding assays for progesterone receptor. In three progesterone receptor positive tumours there was an apparent paradoxical absence of oestrogen receptor; progesterone receptor normally depends on the presence of oestrogen receptor, but these rare tumours may be essentially progesterone receptor positive. It is concluded that this monoclonal antibody is an appropriate reagent for use in the immunohistological determination of progesterone receptor status of breast carcinomas; that it advantageously identifies both the occupied and unoccupied receptor sites; and that it provides information about tumour cell heterogeneity with respect to receptor status.
Increasing evidence shows the importance of young age, estrogen receptor (ER), progesterone receptor (PR) status, and HER-2 expression in patients with breast cancers.
Patients and methods:
We organized an analytic cross-sectional study of 105 women diagnosed with breast cancer who have been operated on between 2008 to 2010. We evaluated age, size, hormone receptor status, HER-2 and P53 expression as possible indicator of lymph node involvement.
There is a direct correlation between positive progesterone receptor status and being younger than 40 (P < 0.05). Also, compared with older women, young women had tumors that were more likely to be large in size and have higher stages (P < 0.05). Furthermore patients with negative progesterone receptor status were more likely to have HER-2 overexpression (P < 0.05). The differences in propensity to lymph node metastasis between hormone receptor statuses were not statically significant.
Although negative progesterone receptor tumors were more likely to have HER-2 overexpression, it is possible that higher stage and larger size breast cancer in younger women is related to positive progesterone receptor status.
breast cancer; estrogen receptor; progesterone receptor; lymph node metastasis; age
The development of familial and sporadic breast cancer is based on genetic alterations of tumour-suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation. To investigate LOH of BRCA1 (17q21) and BRCA2 (13-q12-13) in sporadic breast cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for detection of microsatellite polymorphisms was applied. A total of 137 breast cancer and 15 benign breast specimens with matched normal tissue were examined. Fluorescent-labelled PCR products were analysed in an automated DNA sequencer (ALFTM Pharmacia). Losses at both loci were correlated with different histological types, age, tumour size, lymph node status, grading and steroid hormone receptor expression, [SHR: oestrogen receptor (ER), progesterone receptor (PgR)]. For BRCA1 (D17S855, THRA1, D17S579) losses could be detected in invasive ductal carcinoma (IDC; n = 108) in 32-38%, invasive lobular carcinoma (ILC; n = 19) in 21-42% depending on the marker applied, but not in benign breast tumours (n = 15). Losses of BRCA1 markers correlated with larger tumour size, higher grade, and PgR expression. For BRCA2 (D13S260, D13S267, D13S171) losses could be detected in 108 IDCs in 30-38%, in 19 ILCs in 17-39% depending on the marker applied, but not in benign breast tumours. Losses of BRCA2 markers correlated only with higher grade. Microsatellite analyses combined with detection of fluorescent-labelled PCR products by an automated laser DNA sequencer can be used for routine determination of LOH. In sporadic breast cancer, LOH of BRCA1 of BRCA2 does not add decisive prognostic value as stated for familial breast cancer.
Human breast cancer is classified by gene expression profile into subtypes consisting of two hormone (oestrogen and/or progesterone) receptor-positive types (luminal-like A and luminal-like B) and three hormone receptor-negative types [human epidermal growth factor receptor 2-expressing, basal-like, and unclassified ("normal-like")]. Immunohistochemical surrogate panels are also proposed to potentially identify the molecular-based groups. The present study aimed to apply an immunohistochemical panel (anti-ER, -PR, -ERB-B2, -CK 5/6 and -CK14) in a series of canine malignant mammary tumours to verify the molecular-based classification, its correlation with invasion and grade, and its use as a prognostic aid in veterinary practice.
Thirty-five tumours with luminal pattern (ER+ and PR+) were subgrouped into 13 A type and 22 B type, if ERB-B2 positive or negative. Most luminal-like A and basal-like tumours were grade 1 carcinomas, while the percentage of luminal B tumours was higher in grades 2 and 3 (Pearson Chi-square P = 0.009). No difference in the percentage of molecular subtypes was found between simple and complex/mixed carcinomas (Pearson Chi-square P = 0.47). No significant results were obtained by survival analysis, even if basal-like tumours had a more favourable prognosis than luminal-like lesions.
The panel of antibodies identified only three tumour groups (luminal-like A and B, and basal-like) in the dog. Even though canine mammary tumours may be a model of human breast cancer, the existence of the same carcinoma molecular subtypes in women awaits confirmation. Canine mammary carcinomas show high molecular heterogeneity, which would benefit from a classification based on molecular differences. Stage and grade showed independent associations with survival in the multivariate regression, while molecular subtype grouping and histological type did not show associations. This suggests that caution should be used when applying this classification to the dog, in which invasion and grade supply the most important prognostic information.
Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women.
Materials and Methods
A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles.
Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81).
An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease.
Progesterone, an ovarian steroid hormone, plays a key role in the development and function of the mammary gland, as it also does in the uterus and the ovary. The action of progesterone is mediated through its intracellular cognate receptor, the progesterone receptor (PR), which functions as a transcription factor that regulates gene expression. As with other nuclear receptors, coregulators (coactivators and corepressors) recruited by the liganded or unliganded PR, either to enhance or to suppress transcription activity, modulate the function of the PR. Mutation or aberrant expression of the coregulators might thus affect the normal function of the PR and hence disrupt the normal development of the mammary gland, which may lead to breast cancer.
breast cancer; coactivator; corepressor; progesterone receptor
Progesterone is an ovarian steroid hormone that is essential for normal breast development during puberty and in preparation for lactation. The actions of progesterone are primarily mediated by its high affinity receptors, including the classical progesterone receptor (PR) -A and -B isoforms, located in diverse tissues such as the brain where progesterone controls reproductive behavior, and the breast and reproductive organs. Progestins are frequently prescribed as contraceptives or to alleviate menopausal symptoms, wherein progestin is combined with estrogen as a means to block estrogen-induced endometrial growth. Estrogen is undisputed as a potent breast mitogen, and inhibitors of the estrogen receptor (ER) and estrogen producing enzymes (aromatases) are effective first-line cancer therapies. However, PR action in breast cancer remains controversial. Herein, we review existing evidence from in vitro and in vivo models, and discuss the challenges to defining a role for progesterone in breast cancer.
progesterone; progesterone receptor; breast cancer; estrogen receptor; growth factor; protein kinase; steroid hormone; hormone replacement therapy
Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50% to 64% of human breast cancers express receptors for gonadotropin-releasing hormone (GnRH), which might be used as a target. New targeted therapies are warranted. Recently, we showed that antagonists of gonadotropin-releasing hormone type II (GnRH-II) induce apoptosis in human endometrial and ovarian cancer cells in vitro and in vivo. This was mediated through activation of stress-induced mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK), followed by activation of proapoptotic protein Bax, loss of mitochondrial membrane potential, and activation of caspase-3. In the present study, we analyzed whether GnRH-II antagonists induce apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells that express GnRH receptors. In addition, we ascertained whether knockdown of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling.
Induction of apoptosis was analyzed by measurement of the loss of mitochondrial membrane potential. Apoptotic signaling was measured with quantification of activated MAPK p38 and caspase-3 by using the Western blot technique. GnRH-I receptor protein expression was inhibited by using the antisense knockdown technique. In vivo experiments were performed by using nude mice bearing xenografted human breast tumors.
We showed that treatment of MCF-7 and triple-negative MDA-MB-231 human breast cancer cells with a GnRH-II antagonist results in apoptotic cell death in vitro via activation of stress-activated MAPK p38 and loss of mitochondrial membrane potential. In addition, we showed GnRH-II antagonist-induced activation of caspase-3 in MDA-MB-231 human breast cancer cells. After knockdown of GnRH-I receptor expression, GnRH-II antagonist-induced apoptosis and apoptotic signaling was only slightly reduced, indicating that an additional pathway mediating the effects of GnRH-II antagonists may exist. The GnRH-I receptor seems not to be the only target of GnRH-II antagonists. The antitumor effects of the GnRH-II antagonist could be confirmed in nude mice. The GnRH-II antagonist inhibited the growth of xenotransplants of human breast cancers in nude mice completely, without any apparent side effects.
GnRH-II antagonists seem to be suitable drugs for an efficacious and less-toxic endocrine therapy for breast cancers, including triple-negative breast cancers.
Most breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors.
Clinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers.
BRCA1 carriers aged ≥ 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04).
BRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.
Basal breast cancer comprises ~15% of invasive ductal breast cancers, and presents as high-grade lesions with aggressive clinical behavior. Basal breast carcinomas express p63 and cytokeratin 5 (CK5) antigens characteristic of the myoepithelial lineage, and typically lack Her2/neu and hormone receptor expression. However, there is limited data about the precursor lesions from which they emerge. Here we wished to determine whether comedo-ductal carcinoma in situ (comedo-DCIS), a high-risk in situ breast lesion, serve as precursors for basal-like breast cancer. To determine this link, p63, CK5, Her2/neu, epidermal growth factor receptor (EGFR), estrogen receptor (ER) and progesterone receptor (PgR) expression were analyzed by immunohistochemistry in 17 clinical comedo- and 12 noncomedo-DCIS cases, and in tumors derived from unfractionated and CK5-overexpressing subpopulation (MCF10DCIS.com-CK5high) of MCF10DCIS.com cells, a model representative of clinical comedo-DCIS. p63 and Her2/neu coexpression was analyzed by immunofluorescence double labeling. A novel p63/CK5/Her2/neu expressing subpopulation of cells that are ER−/PgR−/EGFR− were identified in the myoepithelial and luminal areas of clinical comedo-DCIS and tumors derived from unfractionated MCF10DCIS.com and MCF10DCIS.com-CK5high cells. These data suggest that p63 and Her2/neu expressors may share a common precursor intermediate. P63, but not Her2/neu, expression was significantly associated (P = 0.038) with microinvasion/recurrence of clinical comedo-DCIS, and simultaneous expression of p63 and Her2/neu was marginally associated (P = 0.067) with comedo-DCIS. These data suggest that p63/Her2/neu expressing precursor intermediate in comedo-DCIS may provide a cellular basis for emergence of p63+/Her2/neu- or p63+/Her2/neu+ basal-like breast cancer, and that p63/Her2/neu coexpression may serve as biomarkers for identification of this subgroup of basal-like breast cancers.
breast cancer; p63; Her2/neu; cytokeratin; EGFR