Crosstalk of TGF-β and Estrogen Receptor Signaling in Breast Cancer

Estrogen receptor-α (ERα) and transforming growth factor (TGF)-β signaling pathways are major regulators during mammary gland development, function and tumorigenesis. Predominantly, they have opposing roles in proliferation and apoptosis. While ERα signaling supports growth and differentiation and is antiapoptotic, mammary gland epithelia cells are very sensitive to TGF-β—induced cell cycle arrest and apoptosis. Their regulatory pathways intersect, and ERα blocks TGF-β pathway by multiple means, including direct interactions of its signaling components, Smads. However, relatively little is known of the dysfunction of their interactions in cancer. A better understanding would help to develop new strategies for breast cancer treatment.     

Signal Transduction in Transgenic Mouse Models of Human Breast Cancer—Implications for Human Breast Cancer

The advent of genetically engineered mouse models (GEMs) of human breast cancer, have provided important insight into molecular basis or human breast cancer. This review will focus on two of the most extensively studied mouse models for human breast cancer involving mammary gland specific expression of the polyoma middle T (PyV MT) antigen and of the ErbB2. In addition, this review will discuss past and recent advances in understanding relative contribution of the signaling pathways in tumor induction and metastasis by these potent mammary oncogenes.     

Early Discussion of Breast Density and Supplemental Breast Cancer Screening: Is it Possible?

The purpose of this study is to determine whether it is possible to make breast cancer screening more efficient in those with dense breasts. Over 12 states require that patients with dense breasts receive notification about their breast density in lay letters that are sent after the screening mammogram. Some of these letters advise patients to speak with their primary care providers about the possibility of supplemental breast cancer screening. We sought to determine whether primary care providers can discuss breast density and recommend supplemental breast cancer screening using the density of the previous mammography. This would reduce the burden of additional appointments and might increase the number of patients choosing to have supplemental screening. The mammographic breast density of 250 consecutive patients from May 2011 to September 2011 was compared with the immediate prior mammogram. Patients whose prior mammograms were more than 36 months prior or less than 8 months prior to the current exam were excluded, leaving 217 patients. The proportion of patients with breast density change was analyzed. The concordance of breast density between the two exams was assessed and the effects of patient age and the length of time between mammograms were examined. The breast density of the current and most recent prior mammogram was stable for 86.6% of patients. Neither age nor length of time between mammograms affected concordance. Primary care providers can decrease the need for multiple appointments and decrease patient anxiety by discussing breast density and screening choices prior to the patient's screening mammography. The great majority of patients will receive the correct information about their breast density by using a prior report.     

The Multifaceted Roles of Autophagy in Tumors—Implications for Breast Cancer

Autophagy is an evolutionarily conserved lysosomal degradation process that is crucial for adaptation to stress as well as in cellular homeostasis. In cancer, our current understanding has uncovered multifaceted roles for autophagy in tumor initiation and progression. Although genetic evidence corroborates a critical role for autophagy as a tumor suppressor mechanism, autophagy can also promote the survival and fitness of advanced tumors subject to stress, which has important implications during breast cancer progression and metastasis. Here, I discuss the mechanisms and the evidence underlying these diverse roles for autophagy in cancer and speculate on specific circumstances in which autophagy can be most effectively targeted for breast cancer treatment.     

The Effect of Sentinel Node Tumor Burden on Non–Sentinel Node Status and Recurrence Rates in Breast Cancer

Background

Routine axillary lymph node dissection (ALND) after selective sentinel lymphadenectomy (SSL) in the treatment of breast cancer remains controversial. We sought to determine the need for routine ALND by exploring the relationship between sentinel lymph node (SLN) and non-SLN (NSLN) status. We also report our experience with disease relapse in the era of SSL and attempt to correlate this with SLN tumor burden.

Methods

This was a retrospective study of 390 patients with invasive breast cancer treated at a single institution who underwent successful SSL from November 1997 to November 2002.

Results

Of the 390 patients, 115 received both SSL and ALND. The percentage of additional positive NSLNs in the SLN-positive group (34.2%) was significantly higher than in the SLN-negative group (5.1%; P = .0004). The SLN macrometastasis group had a significantly higher rate of positive NSLNs (39.7%) compared with the SLN-negative group (5.1%; P = .0001). Sixteen patients developed recurrences during follow-up, including 6.1% of SLN-positive and 3.3% of SLN-negative patients. Among the SLN macrometastasis group, 8.7% had recurrence, compared with 2.2% of SLN micrometastases over a median follow-up period of 31.1 months. One regional failure developed out of 38 SLN-positive patients who did not undergo ALND.

Conclusions

ALND is recommended for patients with SLN macrometastasis because of a significantly higher incidence of positive NSLNs. Higher recurrence rates are also seen in these patients. However, the role of routine ALND in patients with a low SLN tumor burden remains to be further determined by prospective randomized trials.     

Prognostic Role of Estrogen Receptor α and Estrogen Receptor β in Gastric Cancer

Background  

The presence of estrogen receptor α (ERα) and estrogen receptor β (ERβ) have been reported in cell and tissue level in gastric cancer, but its impact on patients’ survival remains unclear. This study was designed to investigate the expression level of ERα and ERβ and to assess clinical significance of ERα and ERβ expression in gastric cancer.     

Cell Surface β1,4-Galactosyltransferase Function in Mammary Gland Morphogenesis: Insights from Transgenic and Knockout Mouse Models

Development and morphogenesis are profoundly influenced by cell-cell and cell-extracellular matrix (ECM) interactions that are governed by cell surface receptor association with specific ligands. One such receptor is the long isoform of beta1,4-galactosyltransferase I (GalT I), a small proportion of which is targeted to the plasma membrane. Surface-expressed GalT I binds to specific glycoside residues on multiple extracellular ligands, and GalT I binding to specific ligands mediates cell-cell as well as cell-matrix interactions for a variety of cells, including mammary epithelia. Significant insight into surface GalT I function in mammary gland development and morphogenesis has been gained through the analysis of mouse transgenic and knockout models of surface GalT I misexpression. Overexpression of cell surface GalT I leads to impaired lactation as a result of reduced branching and differentiation and elevated apoptosis, while deleting surface GalT I enhances branching and differentiation and reduces apoptosis. These phenotypes can be attributed in large part to altered cell-ECM interactions. The current and future challenges are to use these mouse models to dissect the molecular mechanisms that govern surface GalT I function as a receptor in the normal mammary gland, as well as to assess the potential for surface GalT I misexpression to contribute to disease.     

Is Sentinel Node Biopsy of the Internal Mammary Lymph Nodes Relevant in the Management of Breast Cancer?

The aim of this study was to review the outcomes of a series of breast cancer patients who underwent sentinel node biopsy inclusive of lymphoscintigraphy, and to assess the incidence of internal mammary node (IMN) metastatic positivity at exploration and whether these findings influenced treatment. Between April 2001 and December 2012, 581 breast cancer patients at Princess Alexandra Hospital underwent preoperative lymphoscintigraphy in the course of the performance of sentinel node biopsy. Analysis was performed of those patients who demonstrated radio‐isotope uptake to the IMN chain, and who had sentinel node biopsy of the IMN's and were found to have metastatic involvement. Assessment was made to determine whether the finding of IMN metastases changed the adjuvant systemic management of these patients, and to review complication rates. 95 of 581 (16.4%) patients with preoperative breast lymphoscintigraphy had lymphatic mapping to the IMN chain. 51 (54%) of these patients had IMN chain surgically explored and IMN nodes were found in 35 of these patients (success rate of 69%). Of these, three patients (3/35 = 8.6%) had metastatic involvement of the IMN sentinel node group. All three IMN positive patients received adjuvant breast radiotherapy, chemotherapy, and hormonal therapy. In four patients (7.8%) IMN surgical exploration was complicated by pneumothorax. Only a small proportion of breast cancer patients were found to have metastasic involvement of the IMN chain and which did not significantly change their adjuvant therapy management. These findings suggest that the benefits of exploration of the IMN chain in breast cancer patients are limited and may be outweighed by the risk of complications.     

Intraoperative Findings of Cancer in Delayed Breast Reconstruction: A Dilemma?

Recurrence of breast cancer discovered at the time of reconstruction is rare. However, with increasing numbers of delayed postmastectomy reconstructions being performed, this scenario may become more common. There are no guidelines on how to manage this dilemma. There are two main issues: the effect on the patient and the effect on the reconstruction itself. The authors present two cases and discuss the factors involved in this difficult decision, along with their recommendations.     

Prognostic Value of a Positive-to-negative Change in Hormone Receptor Status after Neoadjuvant Chemotherapy in Patients with Hormone Receptor–positive Breast Cancer

Background

To investigate the prognostic value of positive-to-negative changes in hormone receptor (HR) status after neoadjuvant chemotherapy (NCT) in patients with HR-positive breast cancer.

Methods

Data from 224 stage II?CIII breast cancer patients with positive HR status before NCT who had residual disease in the breast after NCT were collected. HR status of the residual tumors was retested after NCT. A survival analysis was performed in 214 patients with adjuvant endocrine therapy regardless of post-NCT HR status. The survival analysis also examined other clinical and pathologic variables.

Results

In total, 15.2?% of patients had a positive-to-negative change in HR status after NCT, and this change was observed more frequently in HER-2-positive tumors than HER-2-negative tumors (P?=?0.001). In 214 patients who had been treated with adjuvant endocrine therapy regardless of post-NCT HR status, the alteration in HR status was an independent factor for the prediction of a poorer disease-free survival (P?=?0.026) and overall survival (P?P?=?0.003 and P?=?0.001).

Conclusions

The switch of HR status after NCT is remarkable for HR-positive tumors. An HR-negative switch may identify patients who would benefit from alternative systemic therapies.     

Does Cancer Start in the Womb? Altered Mammary Gland Development and Predisposition to Breast Cancer due to in Utero Exposure to Endocrine Disruptors

We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.     

Wnt5a as an Effector of TGFβ in Mammary Development and Cancer

Wnt5a is a member of the Wingless-related/MMTV-integration family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Loss of Wnt5a is associated with early relapse of invasive breast cancer, increased metastasis, and poor survival in humans. It has been shown that TGF-ß directly regulates expression of Wnt5a in mammary gland and that Wnt5a mediates the effects of TGF-ß on branching during mammary gland development. Here we review the evidence suggesting Wnt5a acts as an effector of TGF-ß actions in breast cancer. It is suggested that the tumor suppressive functions of TGF-ß involve Wnt5a-mediated antagonism of Wnt/ß-catenin signaling and limiting the stem cell population. Interactions between TGF-ß and Wnt5a in metastasis appear to be more complex, and may depend on specific cues from the microenvironment as well as activation of specific intracellular signaling pathways.     

Mammary Chain Irradiation in Left-Sided Breast Cancer: Can We Reduce the Risk of Secondary Cancer and Ischaemic Heart Disease with Modern Intensity-Modulated Radiotherapy Techniques?

IntroductionThe aim of the present study was to estimate the impact of the addition of internal mammary chain (IMC) irradiation in node-positive left-sided breast cancer (BC) patients undergoing regional nodal irradiation (RNI) and comparatively evaluate excess relative and absolute risks of radiation-induced lung cancer/BC and ischaemic heart disease for intensity-modulated radiotherapy (IMRT) versus 3D conformal radiotherapy (3D-CRT).MethodsFour treatment plans were created (3D-CRT and IMRT −/+ IMC) for each of the 10 evaluated patients, and estimates of excess relative risk (ERR) and 10-year excess absolute risk (EAR) were calculated for radiation-induced lung cancer/BC and coronary events using linear, linear-exponential and plateau models.ResultsThe addition of IMC irradiation to RNI significantly increased the dose exposure of the heart, lung and contralateral breast using both techniques, increasing ERR for secondary lung cancer (58 vs. 44%, p = 0.002), contralateral BC (49 vs. 31%, p = 0.002) and ischaemic heart disease (41 vs. 27%, p = 0.002, IMRT plans). IMRT significantly reduced the mean cardiac dose and mean lung dose as compared to 3D-CRT, decreasing ERR for major coronary events (64% 3D-CRT vs. 41% IMRT, p = 0.002) and ERR for secondary lung cancer (75 vs. 58%, p = 0.004) in IMC irradiation, without a significant impact on secondary contralateral BC risks.ConclusionAlthough IMC irradiation has been shown to increase survival rates in node-positive BC patients, it increased dose exposure of organs at risk in left-sided BC, resulting in significantly increased risks for secondary lung cancer/contralateral BC and ischaemic heart disease. In this setting, the adoption of IMRT seems advantageous when compared to 3D-CRT.