Coral Omene

Caffeic Acid Phenethyl Ester (CAPE) derived from propolis, a honeybee product, inhibits growth of breast cancer stem cells

SummaryCancer stem cells (CSC) are chemoresistant and implicated in tumor recurrence, metastasis and high patient mortality; thus substances impairing CSC activity, could be invaluable as novel cancer therapeutics. We previously showed that CAPE (caffeic acid phenethyl ester), a component of propolis, a honeybee product, inhibits growth of MDA-MB-231 (MDA-231) cells, mdr gene expression, NF-κB, EGFR, and VEGF. We hypothesized that CAPE also acts by interfering with CSC-mediated effects. We isolated breast CSC (bCSC) from MDA-231 cells, a model of human triple-negative breast cancer, and mouse xenografts. bCSC grow as mammospheres (MMS) and when dissociated into single cells, form MMS again, a sign of self-renewal. bCSC exhibited the characteristic CD44+/CD24-/low phenotype and generated progenitors in the presence of serum, a CSC trait responsible for regenerating tumor mass. CAPE caused dose-dependent bCSC self-renewal inhibition and progenitor formation. Clonal growth on soft agar was inhibited dose-dependently, but apoptosis was not induced as determined by Annexin-V/PI assay. Instead, bCSC were noted to significantly progress from a quiescent cell cycle state in G0/G1 (82%), S phase (12%) to a cycling state with an increase in S phase (41%) and subsequent decrease in G0/G1 (54%). Treatment of bCSC with CAPE (4.5-days) decreased CD44 levels by 95%, while another cell population containing 10-100-fold lower CD44 content concurrently increased. Results suggest that CAPE causes pronounced changes in bCSC characteristics manifested by inhibition of self renewal, progenitor formation, clonal growth in soft agar, and concurrent significant decrease in CD44 content, all signs of decreased malignancy potential.

Phase II trial of RAD001 plus carboplatin in patients with triple-negative metastatic breast cancer.

293 Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. METHODS The primary objective of the study is to determine clinical benefit (complete remission; CR, partial remission; PR and stable disease; SD) and the toxicity of this combination in women with triple negative metastatic breast cancer who had received 0-3 prior chemotherapy regimens for metastatic disease. Prior carboplatin was allowed. Women with treated brain metastasis were eligible. Secondary objectives were to determine progression free survival. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. 5 mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a surprising amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). RESULTS Eleven patients of a planned 25 have been recruited thus far. Median age is 62. Median number of prior regimens is 1. Of the 6 patients assessable for response at this time, four have SD and two have had a PR. 1 SD was achieved in a patient progressing on prior carboplatin at study entry. Five of 7 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. All patients have had treatment held and/or dose reductions secondary to hematological toxicity. There have been no non-hematological grade 3 or 4 toxicities. CONCLUSIONS Clinical benefit was observed in all 6 evaluable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing.

Efficacy of RAD001/carboplatin in triple-negative metastatic breast cancer: A phase II study.

108 Background: Triple-negative breast cancer cells are unable to repair double stranded DNA breaks and have sensitivity to platinum agents. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. RAD001 (oral mTOR inhibitor) and Carboplatin combination may have activity in triple-negative breast cancer. METHODS The primary objective is to estimate clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting >6 months) and toxicity of the combination in triple negative metastatic breast cancer patients who have had 0-3 prior chemotherapy regimens. This design has > 80% power to test the null hypothesis i.e. clinical benefit rate is ≤ 10% vs. alternative hypothesis that clinical benefit rate is ≥ 30%. Prior carboplatin is allowed. Women with treated brain metastasis are eligible. Originally, carboplatin AUC 6 was to be administered every 3 weeks along with daily 5mg of RAD001 with a 3 patient run-in and then 10 mg daily. Due to a surprising amount of thrombocytopenia, the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (no escalation to 10 mg). RESULTS 23 out of 25 patients have been recruited. Median age is 59. Thus far, there have been 1 CR, 5 PRs, 8 SDs and 6 PDs. One SD was achieved in a patient progressing on single agent carboplatin at study entry. Median duration of response is 13 weeks (range: 6-74 weeks). 5 patients had grade 3/4 thrombocytopenia and 4 patients had grade 3 neutropenia (no febrile neutropenia). 13 patients had treatment held and/or dose reductions secondary to hematological toxicity. Since dosing amendment for carboplatin to AUC 4 the regimen has been well tolerated (only 1 patient with grade 3 neutropenia and thrombocytopenia). 1 patient had grade 3 dehydration. The estimated clinical benefit rate is 45% (95% C.I.: 23%, 67%). Median time to progression or death is 85 days from start of treatment. CONCLUSIONS Our study has met the primary end point of demonstrating clinical benefit in triple-negative metastatic breast cancer. Dose-limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. Patient accrual continues at the amended dosing.

A TGFβ–miR-182–BRCA1 axis controls the mammary differentiation hierarchy

TGFβ promotes luminal differentiation of mammary stem cells by suppressing a BRCA1-targeting microRNA. TGFβ directs mammary lineage Breast cancers are often be classified by lineage markers for specific cell types, such as the luminal subtype or the relatively more aggressive myoepithelial (also called basal-like) subtype. Mutations in the protein BRCA1 are associated with the basal-like subtype. The growth factor TGFβ suppresses tumorigenesis in various tissues, but malignant mammary epithelial cells have decreased sensitivity to TGFβ. Using mouse models, Martinez-Ruiz et al. found that loss of TGFβ promoted mammary stem cell self-renewal and skewed differentiation to myoepithelial cells through increased abundance of a microRNA (miR-182) that targets and decreases the translation of BRCA1 transcripts. Expressing BRCA1 or blocking miR-182 restored lineage commitment homeostasis in TGFβ-deficient mammary epithelial cells. The findings link two factors in breast cancer development and may have wider implications for tumorigenesis in other epithelial, ductal tissues (such as the colon, pancreas, and prostate) in which BRCA mutations are also a risk factor. Maintenance of mammary functional capacity during cycles of proliferation and regression depends on appropriate cell fate decisions of mammary progenitor cells to populate an epithelium consisting of secretory luminal cells and contractile myoepithelial cells. It is well established that transforming growth factor–β (TGFβ) restricts mammary epithelial cell proliferation and that sensitivity to TGFβ is decreased in breast cancer. We show that TGFβ also exerts control of mammary progenitor self-renewal and lineage commitment decisions by stringent regulation of breast cancer associated 1 (BRCA1), which controls stem cell self-renewal and lineage commitment. Either genetic depletion of Tgfb1 or transient blockade of TGFβ increased self-renewal of mammary progenitor cells in mice, cultured primary mammary epithelial cells, and also skewed lineage commitment toward the myoepithelial fate. TGFβ stabilized the abundance of BRCA1 by reducing the abundance of microRNA-182 (miR-182). Ectopic expression of BRCA1 or antagonism of miR-182 in cultured TGFβ-deficient mammary epithelial cells restored luminal lineage commitment. These findings reveal that TGFβ modulation of BRCA1 directs mammary epithelial cell fate and, because stem or progenitor cells are thought to be the cell of origin for aggressive breast cancer subtypes, suggest that TGFβ dysregulation during tumorigenesis may promote distinct breast cancer subtypes.

Abstract 5247: Caffeic acid phenethyl ester (CAPE) reverses aggressive breast cancer in the radiation chimera model

CAPE is the major active component of propolis, a widely available, safe, honeybee natural product with anti-inflammatory, antioxidant, and antitumor properties. We have previously shown diverse effects of CAPE in breast cancer. We postulated that CAPE may be useful in chemoprevention for women at high risk for triple-negative breast cancers (TNBC) and evaluated this in a radiation chimera mouse model in which the tumor spectrum is shifted to TNBC. The radiation chimera model consists of surgically clearing the mammary epithelium from the inguinal glands of 3-week old BALB/c mice, the mice were irradiated with 1 Gy or sham irradiated at 10-12 weeks of age, and bilaterally transplanted 3 days later with syngeneic Trp53 null mammary fragments. Mice were placed on a CAPE diet or a control diet at 1 month post transplantation that was maintained for the course of the experiment. Mammary tumor development was monitored by palpation for up to 18 months. The first tumor was resected at 1cm3 and mice monitored for tumor recurrence or second tumor formation. Tumors were immunostained for estrogen receptor (ER) status and ER negative tumors were selected from all the groups for RNA sequencing. No difference in body weight or tumor incidence was observed between mice on the CAPE versus control diet. Host irradiation significantly accelerated tumor growth rate compared to the control sham irradiated mice. CAPE treatment blocked this effect, but did not affect the control tumor growth rate. Resected tumors in CAPE treated mice recurred at significantly longer intervals (average of 40 days in the control group versus 90 days with CAPE treatment) and much less frequently than tumors from mice on a control diet. Mean expression analysis showed that CAPE induces a distinct gene expression pattern in ER negative tumors from irradiated mice. As previously described, the transcriptional profile of ER negative tumors was enriched in immune response genes in tumors from irradiated mice on a control diet. Interestingly, this difference was abrogated in mice on the CAPE diet. These findings support the potential use of CAPE to modify the aggressive behavior of TNBC. This may be due to effects on the immune system in which CAPE acts to re-establish anti tumor immunity. Thus, CAPE may be useful in chemoprevention both for women at high risk for TNBC and to prevent or delay TNBC breast cancer recurrence. Citation Format: Coral O. Omene, Manan Patel, Irineu IllaBochaca, Mary Helen Barcellos-Hoff. Caffeic acid phenethyl ester (CAPE) reverses aggressive breast cancer in the radiation chimera model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5247.

Abstract P1-06-06: Mammary stem cell modulation of wildtype and Trp53 null stem cells by CAPE (caffeic acid phenethyl ester), a potential therapeutic agent

CAPE is the major active component of propolis, a widely available, non-toxic, honeybee natural product with anti-inflammatory, antioxidant, and antitumor properties. We have previously shown that CAPE inhibits growth of breast cancer cells and the tumorigenic potential of breast cancer stem cells. We have identified inhibition of histone deacetylase (HDAC) as one mechanism of action, which suggests that it mediates its effects through epigenetic modifications. We postulated that CAPE may be useful in chemoprevention for women at high risk for triple-negative breast cancers since the cell-of-origin hypothesis states that these cancers likely arise from transformation of mammary stem or progenitor cells, whose self-renewal is maintained via epigenetic states. We tested the effect of CAPE on wildtype (WT) and Trp53 null mammary stem cell (MaSC) self-renewal from BALB/c mice cultured as mammospheres (MMS). Primary mammary epithelial cells were cultured as MMS for 7 days, dissociated into single cells, re-cultured in the presence of CAPE for 7 days and passaged in secondary and tertiary passages without CAPE. MMS frequency and differentiation potential was analyzed using immunofluorescence detection of luminal marker, cytokeratin 18, basal marker, cytokeratin 14, and progesterone receptor (PR). Chromatin states were identified using ATAC-seq and open chromatin areas unique to CAPE treated murine MMS were used for pathway analysis performed by Ingenuity Pathway Analysis, Gene Set Enrichment Analysis and confirmed by Integrative Genome Viewer. CAPE treatment resulted in a dose dependent decrease in both WT and p53 null mammosphere forming efficiency that persisted in secondary and tertiary passages, suggesting reduced self-renewal. CAPE treatment also shifted differentiation from predominantly basal K14 to luminal K18-positive in both WT and p53 null MMS and increased PR expression in WT MMS. ATAC-seq of CAPE treated WT MMS showed significant pathway enrichment for p53 signaling, SOX2 signaling, and enrichment of open chromatin for several genes including the SMARCA4 gene, which regulates transcription of genes involved in stem cell renewal. ATAC-seq of CAPE treated Trp53 null MMS showed that genes defining early and late response to estrogen were particularly important. Significant canonical pathways included Aryl hydrocarbon receptor signaling, whose upregulation results in inhibition of self renewal and has been targeted as a potential drug target for estrogen receptor negative breast cancer. The integrin signaling pathway was also highly enriched. These data suggest that CAPE both inhibits MaSC self-renewal and shifts the lineage commitment to a luminal, ER + lineage. ATAC-seq demonstrated genomic effects that are important in differentiation, SC renewal and adhesion. These data suggest that CAPE may have an effect on lineage commitment in support of our chemoprevention strategy to reduce triple-negative breast cancer. Citation Format: Omene C, Patel M, Kannan K, Heguy A, Barcellos-Hoff MH. Mammary stem cell modulation of wildtype and Trp53 null stem cells by CAPE (caffeic acid phenethyl ester), a potential therapeutic agent. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-06-06.

Abstract 4232: CAPE (caffeic acid phenethyl ester) induces a mammary stem cell lineage restriction to a luminal phenotype via chromatin remodeling

Propolis, and its active component, CAPE, is a widely available, safe, honeybee natural product with anti-inflammatory, antioxidant, and antitumor properties. We have previously shown that CAPE, inhibits 1) growth of ER+/PR+, ER-/PR- and Her2 + breast cancer cells, 2) the tumorigenic potential of breast cancer stem cells, and 3) mediates its effects through epigenetic modifications via HDAC inhibition, resulting among others, in increased ER in ER- cells. We postulated that CAPE may be useful in chemoprevention for women at high risk for triple-negative breast cancers (TNBC). The cell-of-origin hypothesis states that these cancers arise from transformation of mammary stem cells (SC). We tested the ability of CAPE to inhibit SC self-renewal in murine mammary epithelial cells (MEC) and a human breast epithelial cell line (MCF10A). MEC isolated from BALB/c mice were cultured as mammospheres (MMS) for 7 days in ULA 96 well plates using media containing 5% FBS and 5% Matrigel. MMS were dissociated into single cells, recultured in the presence of CAPE for 7 days and passaged in secondary and tertiary passages in media alone. Alternatively, MCF10A transfected with a Let7c-miRNA reporter were sorted for Let7c-negative cells, and similarly cultured with CAPE. Murine MMS were analyzed for luminal marker, K18, basal marker K14, or progesterone receptor (PR) using immunofluorescence. Open chromatin states were identified using ATAC-seq and peaks were independently called using PeakDeck. Open chromatin areas unique to CAPE treated murine MMS were used for pathway analysis performed by Ingenuity Pathway Analysis and confirmed by Integrative Genome Viewer. CAPE treatment resulted in a dose dependent decrease in mammosphere forming efficiency that persisted in secondary and tertiary passages, indicating reduced self-renewal. CAPE shifted the cells within murine MMS from predominantly K14 to K18-positive and increased PR expression. Interestingly, ATAC-seq showed enrichment of open chromatin of the SMARCA4 gene in the exonic region. SMARCA4 is a chromatin remodeling gene that is involved in SWI/SNF complex and alters the positioning of the nucleosome, it is thought to regulate transcription of certain genes by altering the chromatin structure around those genes. In addition, SMARCA4 can bind BRCA1, and regulate the expression of the tumorigenic breast cancer SC marker, CD44. These data indicate that CAPE both inhibited mammary SC self-renewal and shifted the lineage commitment to a luminal lineage. ATAC-seq demonstrated effects at the chromatin level that may regulate the SMARCA4 gene, which controls the transcription of many genes involved in stem cell renewal, pluripotency, and embryonic development and is differentially expressed in the luminal phenotype of human MEC. Thus, CAPE may have an effect on lineage commitment in agreement with our chemoprevention strategy to reduce TNBC breast cancer development. Citation Format: Coral O. Omene, Manan Patel, Kasthuri Kannan, Adriana Heguy, Mary Helen Barcellos-Hoff. CAPE (caffeic acid phenethyl ester) induces a mammary stem cell lineage restriction to a luminal phenotype via chromatin remodeling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4232. doi:10.1158/1538-7445.AM2015-4232

Abstract 3344: CAPE-induced inhibition of breast cancer stem cells (CSC) self-renewal and growth by differentiation to a less malignant phenotype

Introduction: Cancer stem cells (CSC) are implicated in tumor metastasis, recurrence, and high patient mortality, thus, substances impairing their activity, e.g., self-renewal, could be invaluable as novel cancer therapeutics. We propose that CAPE (caffeic acid phenethyl ester), a component of propolis, a honeybee product, could be such an agent. CSC are known for their chemoresistance. We previously showed that CAPE inhibits growth of MDA-231 (231) cells, a model of human triple-negative breast cancer, multidrug resistance gene expression, NF-κB, EGFR, and VEGF. We hypothesized that CAPE could also affect CSC-mediated effects. Methods: We isolated CSC from 231 cells and mouse xenografts, and propagated them in low adherence tissue culture plates without serum. CSC characteristics, ie Hoechst 33342 dye exclusion and CD44+/CD24-/low/EpCAMlow phenotype, were assessed by flow cytometry, while clonal growth was assayed in soft agar. CSC were treated with CAPE (0-40 μM) for 4 or 7 days. Apoptosis was assessed by Annexin V/propidium iodide staining. Cell cycle analysis was done according to standard protocol and analysis by ModFit software. Results: 231-derived CSC grow as mammospheres (MMS), and when dissociated into single cells, form MMS again. This process was repeated for many generations and is considered a sign of self-renewal. These cells excluded Hoechst 33342 dye, exhibited characteristic CD44+/CD24-/low/EpCAMlow phenotype, and generated progenitors in presence of serum, a CSC trait responsible for regenerating tumor mass. CAPE inhibited CSC self-renewal, progenitors’ generation, and growth of CSC-derived tumor cells. Treatment of CSC with CAPE for 4.5 days decreased CD44 levels by ∼95%, while another cell population containing 10-100-fold lower CD44 content concurrently increased. Incubation of CSC with different CAPE doses for 4 days caused dose-dependent cell growth inhibition. After pre-treating cells with CAPE, the same numbers of live cells were taken from each well and plated on soft agar. Clonal growth was also inhibited in a dose-dependent fashion, but apoptosis was not induced as determined by Annexin V/PI assay. Instead, CSC were noted to significantly progress from a quiescent cell cycle state in G0/G1 (82%), S phase (12%) to a cycling state with an increase in S phase (41%) and subsequent decrease in G0/G1 (54%). Conclusions: These results suggest that CAPE causes pronounced changes in CSC characteristics manifested by inhibition of clonal growth in soft agar and concurrent significant decrease in CD44 content, a sign of decreased potential of malignancy. This conclusion is strengthened by the observation that the CSC are induced into a more differentiated state that is less malignant after CAPE treatment. Our results strongly suggest that CAPE could be an inhibitor of CSC making them more susceptible to chemotherapy. [grants BCTR0600476 & ES00260] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2011-3344

P1-17-07: Phase II Trial of RAD001 Plus Carboplatin in Patients with Triple-Negative Metastatic Breast Cancer.

Background: RAD001 is an oral mTOR inhibitor that has exhibited activity in breast cancer. Triple negative breast cancer cells are unable to repair double stranded DNA breaks and hence have sensitivity to platinum agents that cause interstrand cross-links. Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in at least two different breast cancer cell lines (including ER/PR negative cell lines). We propose that combination RAD001 and carboplatin may have activity in triple-negative breast cancer. Methods: The primary objective of the study is to determine clinical benefit (complete remission (CR) + partial remission (PR) + stable disease (SD)) and the toxicity of this combination in women with triple negative metastatic breast cancer who have had 0–3 prior chemotherapy regimens for metastatic disease. Secondary objectives are to determine progression free survival as well as investigating the relationship between pretreatment sensitivity (biopsy at baseline) and clinical response (biopsy post 2 cycles) using IHC staining for abundance of key proteins in the Akt-mTOR pathway and their activity using surrogate phosphorylation site-specific antibodies (Akt and phospho-serine 473, phospho-threonine and phospho-threonine 308 Akt; mTOR and phospho-serine 2448 mTOR; ribosome protein S6 kinase (S6K) and phospho-threonine 378 S6K; 4E-BP1 and phospho-serine 65 4E-BP1). Prior carboplatin is allowed. Women with treated brain metastasis are eligible. According to the original study plan, carboplatin AUC 6, was to be given intravenously every three weeks. Five mg of RAD001 was to be given daily with a 3 patient run-in and then 10 mg daily if there were no dose-limiting toxicities. Due to a unexpected amount of thrombocytopenia with this combination the dose of carboplatin was first amended to AUC 5 and most recently to AUC 4 with 5 mg of RAD001 (and no plan to escalate to 10 mg). Results: Fourteen patients of a planned 25 have been recruited thus far. Median age is 58.5. Median number of prior regimens is 2 (0-3). Of the 7 patients assessable for response at this time, there have been 2 PR9s and 5 patients with SD. One SD was achieved in a patient progressing on single agent carboplatin at study entry. Median duration of SD + PR is 28.5 weeks (5 patients have ongoing response ranging from 8–46.5 weeks). Five of 8 patients assessable for toxicity had grade 3 or 4 thrombocytopenia and 2 patients had grade 3 neutropenia. No cases of febrile neutropenia were observed. Four patients have required blood transfusion and one patient has required platelet transfusion. All patients have had treatment held and/or dose reductions secondary to hematological toxicity, however, since amended carboplatin dose the regimen has been very well tolerated with only one out of six patients) with grade 3 neutropenia and grade 3 thrombocytopenia. There have been no non-hematological grade 3 or 4 toxicities. Conclusions: Clinical benefit was observed in all 7 assessable patients. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. We continue to accrue study subjects at the amended dosing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-07.

Chapter 42 – The Differences between Male and Female Breast Cancer

Publisher Summary Breast cancer is a disease that develops in both men and women. While there are similarities in this disease between the two genders, there are also differences. It is the most commonly diagnosed malignancy in women, second only to skin cancer, with associated immense socioeconomic ramifications. However, in men, breast cancer is rare. Is this disease biologically different in men and women? Or is it similar between the sexes with the same etiologic, prognostic, and clinical features? The data to date suggest that breast cancer in men is fundamentally identical to breast cancer in women with few exceptions. This chapter explores the classic features of breast cancer in both sexes, highlighting the differences and the similarities between them and what is as yet unknown. Despite the clear disparity in the incidence of breast cancer between the sexes, once it occurs in either a man or a woman its clinical presentation, pathologic appearance, response to treatment, and overall prognosis are not that different. Given that breast cancer in women is a prevalent disease and the second leading cause of cancer-related death, there is a great socioeconomic burden. This has led to extensive research into this disease. The risk factors, prognostic factors, and treatment algorithm have all been thoroughly explored, and clinicians have resources to draw on when treating their female patients. This is the major difference between the sexes. Breast cancer is a rarity in males; therefore, it is much less studied. Although there have been some emerging data in male breast cancer, most knowledge and treatment approaches for this disease in males come from the extrapolation of information about female patients with breast cancer.