SUMMARYFOXA1, estrogen receptor a (ERa) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the morphogenesis of various organs, with ERa and GATA3 being established regulators of mammary gland development. Interdependency between these three factors in breast cancer and normal mammary development has been suggested, but the specific role for FOXA1 is not known. Herein, we report that Foxa1 deficiency causes a defect in hormone-induced mammary ductal invasion associated with a loss of terminal end bud formation and ERa expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERa and GATA3 deficiency, Foxa1 null glands form milk-producing alveoli, indicating that the defect is restricted to expansion of the ductal epithelium, further emphasizing the novel role for FOXA1 in mammary morphogenesis. Using breast cancer cell lines, we also demonstrate that FOXA1 regulates ERa expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERa-positive breast cancers, at least in part, through its control of ERa expression.

Breast cancer is a heterogeneous disease comprised of multiple subtypes. Luminal subtype tumors confer a more favorable patient prognosis, which is in part, attributed to estrogen receptor-α (ER) positivity and anti-hormone responsiveness. Expression of the forkhead box transcription factor, FOXA1, similarly correlates with the luminal subtype and patient survival, but is also present in a subset of ER-negative tumors. FOXA1 is also consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, breast cancer cell lines representing the basal subtype do not express FOXA1. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favorable prognosis, we performed cDNA microarray analyses on FOXA1-positive, ER-positive (MCF7, T47D) or FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) luminal cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Gene Set Enrichment Analyses (GSEA) revealed FOXA1 silencing causes a partial transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to a subset of both luminal and basal genes within luminal breast cancer cells, and loss of FOXA1 increases enhancer RNA (eRNA) transcription for a representative basal gene (CD58). These data suggest FOXA1 directly represses basal signature genes. Functionally, FOXA1 silencing increases migration and invasion of luminal cancer cells, both characteristics of basal subtype cells. We conclude FOXA1 controls plasticity between basal and luminal breast cancer cells, not only by inducing luminal genes, but also by repressing the basal phenotype, and thus aggressiveness. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward more aggressive cancers.

Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.HER2/Neu/ErbB2 (epidermal growth factor receptor 2) is a member of the epidermal growth factor receptor (EGFR) 2 family that is amplified and overexpressed in 20 -30% of breast cancers. HER2/ErbB2-positive breast cancer yields a poor patient prognosis because of a high incidence of metastases and intrinsic resistance to endocrine and conventional chemotherapy (1). ErbB2 is the preferred heterodimerization partner for EGFR, ErbB3, and ErbB4 (2). The large range of downstream signaling targets induced by ErbB2-containing heterodimers permits this receptor and its partners to modulate a wide array of cellular processes. Of these, the nonreceptor tyrosine kinase Src, PI3K, and MAPK pathways are the most studied in mediating ErbB2 responsiveness, which includes increased proliferation, survival, motility, and invasion (3).ErbB2-induced cell migration and invasion, and hence metastatic potential, requires activation of Src and its downstream signaling pathways (4). Src also positively provides feedback and stabilizes competent ErbB2/ErbB3 heterocomplexes to enhance PI3K/Akt signaling (5). ErbB2 overexpression in MDA-MB-435 cells enhances formation of metastases by increasing Src synthesis and decreasing its degradation by calpain (6). Similarly, signaling from ErbB2 to Akt is necessary to promote metastatic potential because attenuation of the Akt pathway by pharmacological inhibitors or RNAi decreases the formation of metastases by the ErbB2-dependent 21T breast cancer cell line (7).

Summary Triple-negative breast cancer (TNBC) comprises 10-15% of newly-diagnosed breast cancer and lacks expression of the estrogen, progesterone and HER-2/neu receptors. Many such tumors are basal-like, a molecular intrinsic subtype of breast cancer associated with poor clinical outcomes. Patients with early-stage basal-like TNBC are at a high risk of relapse and may therefore benefit from novel therapies, including immunotherapy. MUC1 is a tumor antigen expressed on adenocarcinomas and represents an ideal target for MUC1-based vaccination. We evaluated 52 cases of early-stage basal-like TNBC for MUC1 expression by immunohistochemistry. The intensity of staining was graded according to the intensity (negative (0), positive (1) or strongly-positive (2) and percent (0 to 100%) of tumor cells staining for MUC1. An overall score of 0 to 2.0 was calculated for each case by multiplying the intensity of staining by the percent of tumor cells staining positively. Four staining patterns for MUC1 were identified: apical, cytoplasmic, membranous, and combination. Forty nine of the 52 cases of basal-like TNBC (94%) were positive for MUC1 expression. The mean score was 0.90 (range 0 - 1.9). Cases were evenly distributed over this range, where most (67%) exhibited moderate to strong MUC1 expression (score 0.5 to 1.90), 27% demonstrated weak MUC1 expression, and 6% lacked MUC1 expression. There was a significant difference in MUC1 score and percent MUC1+ cells in favor of the combination pattern. This study indicates that a large proportion of early-stage basal-like TNBC expresses MUC1 and provides a rationale for MUC1-based immunotherapy in this high-risk patient cohort.

We describe a 91-year-old woman with a clinical history of invasive ductal carcinoma of the breast diagnosed in 1991 who was admitted because of dizziness, poor appetite, and some swelling and tenderness over her cheeks. The patient's initial work up revealed a 5-cm well-demarcated hypodense solid lesion in her spleen with abnormally intense uptake on PET/CT scan raising suspicion for malignancy i.e. breast metastasis versus lymphoma. Further review demonstrated the presence of this splenic lesion, though slightly smaller, on a CT scan from ten years earlier (2000). An ultrasonographic guided core needle splenic biopsy was performed and the pathology result revealed histological findings compatible with inflammatory pseudotumor of the spleen. As a result, unnecessary splenectomy was avoided.

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We present a rare case of pagetoid reticulosis arising in a five year old white boy. He had a history of a large chronic erythematous, scaly patch on his left buttock that had shown intermittent partial response to a topical anti-fungal medication. A punch biopsy revealed dramatic epidermal hyperplasia, with parakeratosis and prominent exocytosis of single and clustered mononuclear cells (Pautrier's microabscesses) into the epidermis. Some of these exhibited hyperchromatic nuclei with irregular contours. They stained prominently for CD3, CD4 and CD8, with a predominance of CD8 + cells. T cell receptor gene rearrangement by PCR was negative for a clonal process on a second biopsy that was sub diagnostic on routine sections.Pagetoid reticulosis is an indolent, unilesional variant of mycosis fungoides, in which the atypical T cells may express a CD4−/CD8+ phenotype. This is in contrast to primary cutaneous epidermotropic CD8+ cytotoxic T-cell lymphoma, which is often very aggressive with a poor outcome. Pagetoid reticulosis is exceedingly rare in children and adolescents. Two features predict a benign course in this 5 year old child: the unilesional clinical presentation and the CD8 predominance of the epidermal lymphocytes.

The 7th edition of the AJCC Cancer Staging Manual represents a dramatic shift in the way that cutaneous squamous cell carcinoma (cSCC) is staged, in that it is first attempt to incorporate evidence-based medicine into the staging guidelines for cSCC. In our opinion, the changes made to the seventh edition represent a significant improvement over previous editions and will ultimately lead to improved patient stratification, more accurate prognostic data, and a better framework to guide clinical decision making. However, there are a number of issues within the latest guidelines that require clarification or are impractical for clinical practice. The purpose of this paper is to highlight the key changes to the 6th edition staging manual as they pertain to cSCC, to point out impractical component of the 7th edition and/or aspects that require further clarification, and to make recommendations that address any current shortcomings to improve subsequent editions. Specific focus will be given to the inclusion of separate guidelines for cSCC and Merkel cell carcinoma (MCC), the incorporation of high-risk factors as modifiers of T stage, the addition of new guidelines for advanced T stage, and the changes in stratification of lymph node status. This paper is modified from a more comprehensive treatment of the staging of nonmelanoma skin cancer by Warner and Cockerell entitled “The new 7th edition American joint committee on cancer staging of cutaneous nonmelanoma skin cancer: a critical review,” in the American Journal of Clinical Dermatology (paper accepted, pending publication).