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1.  Effects of A Breast-Health Herbal Formula Supplement on Estrogen Metabolism in Pre- and Post-Menopausal Women not Taking Hormonal Contraceptives or Supplements: A Randomized Controlled Trial 
Both indole-3-carbinol and dietary lignans have beneficial effects on estrogen metabolism and breast cancer risk. There is no published literature on the effects of a combination product. This study was designed to investigate the impact of a combination product on estrogen metabolism. The major trial objective was to determine whether a breast health supplement containing indole-3-carbinol and hydroxymatairesinol lignan would alter estrogen metabolism to favour C-2 hydroxylation and reduce C-16 hydroxylation. Higher concentrations of C-2 metabolites and lower concentrations of C-16 metabolites may reduce breast cancer risk and risk for other hormonally-related cancers.
Forty-seven pre-menopausal and forty-nine post-menopausal women were recruited for this study, and were divided by random allocation into treatment and placebo group. The treatment supplement contained HMR lignan, indole-3-carbinol, calcium glucarate, milk thistle, Schisandra chinesis and stinging nettle, and each woman consumed either treatment or placebo for 28 days. At day 0 and day 28, blood samples were analysed for serum enterolactone concentrations, and first morning random urine samples were assessed for estrogen metabolites. Repeated measures ANOVA statistical testing was performed.
In pre-menopausal women, treatment supplementation resulted in a significant increase (P < 0.05) in urinary 2-OHE concentrations and in the 2:16α-OHE ratio. In post-menopausal women, treatment supplementation resulted in a significant increase in urinary 2-OHE concentrations. In pre- and post-menopausal women combined, treatment supplementation produced a significant increase in urinary 2-OHE concentration and a trend (P = 0.074) toward an increased 2:16α-OHE ratio. There were no significant increases in serum enterolactone concentrations in the treatment or placebo groups.
Supplementation with a mixture of indole-3-carbinol and HMR lignan in women significantly increased estrogen C-2 hydroxylation. This may constitute a mechanism for the reduction of breast cancer risk as well as risk for other estrogen-related cancers. Further studies with higher numbers of subjects are indicated.
Trial registration registration #NCT01089049.
PMCID: PMC3018890  PMID: 21234288
herbal supplement; breast health; estrogen metabolites
2.  Phytohemagglutinin-Induced Mitotic Index in Blood Lymphocytes: A Potential Biomarker for Breast Cancer Risk 
Cell proliferation is associated with the pathogenesis of cancer because it provides opportunities for accumulating genetic mutations. However, biomarkers of cell proliferation in response to environmental stimuli have not been adequately explored for breast cancer risk.
In a case-control study of 200 breast cancer patients and 360 healthy controls, we investigated the association between phytohemagglutinin (PHA)-induced mitotic index in blood lymphocyte and breast cancer risk.
Having high mitotic index (>3.19%) was associated with an increased risk of breast cancer, with adjusted odds ratios (95% confidence interval) of 1.54 (1.03–2.30) and 2.03 (1.18–3.57) for all women and post-menopausal women, respectively. Mitotic index was correlated with some reproductive factors and body mass index in controls.
Our data suggest increased PHA-induced mitotic index in blood lymphocytes is associated with an increased breast cancer risk and that this association may be modulated by reproductive and other hormones.
PMCID: PMC3018891  PMID: 21234289
breast cancer; mitogens; mitotic index; biomarker; cell proliferation; lymphocytes
3.  Early Stage Breast Cancer and Its Association with Diet and Exercise-Related Perceptions and Behaviors to Prevent Recurrence 
The favorable prognosis for early stage breast cancer survivors may be a reason for the minimal research regarding their quality of life. Prior research has observed more long-term weight gain among early stage survivors compared to cancer-free women of a similar age. It would be useful to study survivors’ perceptions and reported behaviors regarding diet and exercise to see if there is a correlation with previous studies.
A sample of 700 breast cancer survivors from Ohio and Michigan was randomly selected from the Northwest Ohio affiliate of the Susan G. Komen For the Cure mailing list and sent a survey for completion.
389 survivors completed the survey and among Stage 1 (50/197 = 25.4%) and Stage 2 survivors (24/105 = 22.9%), a small proportion had a positive correlation between self-reported dietary behaviors and their perceived benefits of eating fruits and vegetables. Similar correlations were observed between their self-reported exercise behaviors and their perceived benefits of exercise (Stage 1: 36/197 = 18.3%, Stage 2: 18/105 = 17.1%).
Regardless of stage, a small proportion of survivors’ self-reported dietary and exercise behaviors match their perceived benefits of diet and exercise. Factors such as access, motivation, and lack of co-morbidities among early stage survivors may prevent them from living healthier post-diagnosis. More thorough dietary and clinical measurements will provide greater certainty. Thus, innovative, sustainable programs must be accessible and provide motivation and social support from family, friends, and other survivors to truly improve quality of life.
PMCID: PMC2999512  PMID: 21151861
breast cancer; diet; exercise; activity
4.  Assessment of Breast Cancer Risk Based on Mammary Gland Volume Measured with CT 
We investigated the relationship between mammary gland volume (MGV) of the breast as measured with three-dimensional chest computed tomography (CT) and breast cancer risk. Univariate analysis was used to assess the relationship between MGV and known risk factors in 427 healthy women. A case control study (97 cases and 194 controls) was conducted to assess breast cancer risk. MGV was significantly smaller for postmenopausal women than for premenopausal women, and was significantly larger for women with a family history of breast cancer than for women without. MGV, body mass index (BMI), and rate of family history of breast cancer were significantly higher among breast cancer patients than among healthy women, and number of deliveries was significantly lower among breast cancer patients. In postmenopausal women, age at menarche was significantly younger for breast cancer patients. MGV correlated well with breast cancer risk factors. The highest odds ratio was 4.9 for premenopausal women with the largest MGV. Regardless of menopausal status, the greater the MGV, the higher the odds ratio. Our results constitute the first reliable data on the relationship between MGV and breast cancer obtained through exact volume analysis.
PMCID: PMC2999513  PMID: 21151862
mammographic density; mammary gland volume; breast cancer risk factor; breast cancer risk
5.  Invasive Lobular Carcinomas Do Not Express Basal Cytokeratin Markers CK5/6, CK14 and CK17 
The expression of basal cytokeratin markers CK5/6 in breast carcinomas has been associated with high histological grade and poor clinical outcome. A previous study has shown that CK5/6 can be detected in up to 17% of invasive lobular carcinomas (ILC). Here we study the expression of three basal cytokeratin markers (CK5/6, CK14, and CK17) in 53 ILC cases diagnosed by histology and lack of E-cadherin expression. Among them, 42 were classic lobular carcinomas, 6 were tubular-lobular carcinoma, and 5 were pleomorphic lobular carcinomas. There was no significant difference among these three groups in patients’ age, tumor size, uni- and multi-focality, expression of ER and PR, lymphovascular invasion, perineural invasion and lymph node metastasis. The only statistically different factor was HER2 over-expression, which was observed only in pleomorphic ILC (P = 0.0073). None of the 53 cases expressed CK5/6, CK14 or CK17; and 51/53 cases expressed luminal markers CK8 and CK18, and the two negative cases were both classic lobular carcinoma, with positivity for ER and PR. In conclusion, all 53 cases of ILC failed to show expression by any of the three basal CK markers, suggesting that very few ILC will demonstrate a basal phenotype when assessed by immunohistochemistry (IHC). More studies are needed to investigate molecular classification in lobular carcinoma of the breast.
PMCID: PMC2999514  PMID: 21151863
lobular carcinoma of the breast; CK5; CK14 and CK17
6.  Apolipoprotein E Allelic Frequency Altered in Women with Early-onset Breast Cancer 
Among women, the most prevalent type of cancer is breast cancer, affecting 1 out of every 8 women in the United States; in Puerto Rico, 70 out of every 100,000 will develop some type of breast cancer. Therefore, a better understand of the potential risk factors for breast cancer could lead to the development of early detection tools. A gene that has been proposed as a risk factor in several populations around the world is Apolipoprotein E (apoE). ApoE functions as a mechanism of transport for lipoproteins and cholesterol throughout the body, with 3 main isoforms present in humans (apoE2, apoE3, and apoE4). Whether or not apoE4 is a risk factor for breast cancer remains controversial. Previous studies have either included test subjects of all ages (20–80) or have focused on late-onset (after age 50) breast cancer; none has concentrated specifically on early-onset (aged 50 and younger) breast cancer. The objectives of this study was to examine (in a Puerto Rican population) the differences in the relative frequency of occurrence of apoE4 in non-breast cancer versus breast cancer patients and to examine, as well, the potential differences of same in early- versus late-onset patients. We found an increased frequency of apoE4 (odds ratio 2.15) only in early-onset breast cancer survivors, which is similar to the findings of those studies that combined or adjusted for age as well as for an association between apoE4 and decreased tumor size. ApoE is also a potential risk factor for long-term cognitive effects after chemotherapy and affects response to hormone replacement. Our data supports the theory that knowing the apoE genotype of women who are at risk of developing breast cancer may be beneficial, as such knowledge would aid in the prediction of tumor size and the development of treatment regimens.
PMCID: PMC2914274  PMID: 20697532
breast cancer; apoe; puerto rican; risk factor; early-onset
7.  The Expression Patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by Immunohistochemical Analysis in Breast Cancer Cell Lines 
The molecular classification for breast carcinomas has been used in clinical studies with a simple surrogate panel of immunohistochemistry (IHC) markers. The objective of this current project was to study the molecular classification of commonly used breast cancer cell lines by IHC analysis. Seventeen breast cancer cell lines were harvested, fixed in formalin and made into cell blocks. IHC analyses were performed on each cell block with antibodies to estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, CK5/6, Ki-67 and androgen receptor (AR). Among the 17 cell lines, MCF-7 and ZR-75-1 fell to Luminal A subtype; BT-474 to Luminal B subtype; SKBR-3, MDA-MD-435 and AU 565 to HER2 over-expression subtype; MDA-MB-231, MCF-12A, HBL 101, HS 598 T, MCF-10A, MCF-10F, BT-20, 468 and BT-483 to basal subtype. MDA-MB-453 belonged to Unclassified subtype. Since each subtype defined by this IHC-based molecular classification does show a distinct clinical outcome, attention should be paid when choosing a cell line for any study.
PMCID: PMC2914277  PMID: 20697531
molecular classification; breast cancer; cell lines; immunohistochemistry
8.  Does Race Affect Outcomes in Triple Negative Breast Cancer? 
There is discordance among studies assessing the impact of race on outcome of patients with Triple Negative Breast Cancer (TNBC). We assessed survival outcomes for African American (AA) versus Caucasian (CA) women with TNBC treated at an urban cancer center in Memphis, TN with a predominant AA patient population.
Patients with Stage I-III TNBC were identified from our breast database. Event free survival (EFS) and Breast cancer specific survival (BCSS) were the primary outcome measures. Cox proportional hazards models were fitted for EFS and BCSS.
Of the 124 patients, 71% were AA. No significant association between race and stage (P = 0.21) or menopausal status (P = 0.15) was observed. Median age at diagnosis was significantly lower for AA versus CA women (49.5 vs. 55 years, P = 0.024). 92% of the patients received standard neo/adjuvant chemotherapy, with no significant difference in duration and type of chemotherapy between the races. With a median follow up of 23 months, 28% of AA vs. 19% of CA women had an event (P = 0.37). 3 year EFS and BCSS trended favorably towards CA race (77% vs. 64%, log rank P = 0.20 and 92% vs. 76%, P = 0.13 respectively) with a similar trend noted on multiple variable modeling (EFS: HR 0.62, P = 0.29; BCSS: HR 0.36, P = 0.18). AA women ≥50 years at diagnosis had a significantly worse BCSS than the CA women in that age group (P = 0.012).
Older AA women with TNBC have a significantly worse breast cancer specific survival than their CA counterparts. Overall, there is a trend towards lower survival for AA women compared to Caucasians despite uniformity of tumor phenotype and treatment. The high early event rate, irrespective of race, underscores the need for effective therapies for women with TNBC.
PMCID: PMC2914275  PMID: 20697530
triple negative; racial differences; biology; uniform treatment; survival
9.  Detection of Provasopressin in Invasive and Non-invasive (DCIS) Human Breast Cancer Using a Monoclonal Antibody Directed Against the C-terminus (MAG1) 
The provasopressin protein (proAVP) is expressed by invasive breast cancer and non-invasive breast cancer, or ductal carcinoma in situ (DCIS). Here we demonstrate the ability of the monoclonal antibody MAG1 directed against the C-terminal end of proAVP to identify proAVP in all cases examined of human invasive cancer and DCIS (35 and 26, respectively). Tissues were chosen to represent a relevant variation in tumor type, grade, patient age, and menopausal status. By comparison, there was 65% positive staining for estrogen receptor, 61% for progesterone receptor, 67% for nuclear p53, and 39% for c-Erb-B2 with the invasive breast cancer sections. Reaction with the normal tissue types examined (67) was restricted to the vasopressinergic magnocellular neurons of the hypothalamus, where provasopressin is normally produced, and the posterior pituitary, where these neurons terminate. The breast epithelial tissue sections on the tissue microarray did not react with MAG1. Previously, we demonstrated that polyclonal antibodies to proAVP detected that protein in all breast cancer samples examined, but there was no reaction with breast tissue containing fibrocystic disease. The results presented here not only expand upon those earlier results, but they also demonstrate the specificity and effectiveness of what may be considered a more clinically-relevant agent. Thus, proAVP appears to be an attractive target for the detection of invasive breast cancer and DCIS, and these results suggest that MAG1 may be a beneficial tool for use in the development of such strategies.
PMCID: PMC2914276  PMID: 20697529
invasive breast cancer; ductal carcinoma in situ (DCIS); vasopressin; provasopressin; monoclonal antibody
10.  Analysis of the Relationship Between Diet and Exercise Beliefs and Actual Behaviors Among Breast Cancer Survivors in Northwest Ohio 
Studies have shown that a diet high in fruit and vegetable intake, as well as a routine including daily exercise or physical activity, can independently affect relapse rates and survivorship in breast cancer patients. Fruits and vegetables contain powerful anti-oxidant molecules, capable of preventing tumor formation and proliferation. Exercise can lower circulating levels of estrogen, the female hormone responsible for tumor proliferation in the estrogen-sensitive form of the disease. The most beneficial results have been shown in women who exercise and consume a diet rich in fruits and vegetables. We studied the attitudes towards and behaviors related to fruit and vegetable intake and exercise in a cohort of breast cancer survivors in northwest Ohio.
Materials and Methods:
Data were gathered from a survey sent out by the Northwest Ohio Branch of the Susan G. Komen For the Cure Foundation. We assessed and evaluated survivors’ self-reported beliefs, attitudes, and behaviors regarding exercise and fruit and vegetable intake.
Nearly half of the survivors (46.5%) reported being unsure or in disagreement with the statement “Eating at least 5 servings of fruits and/or vegetables per day will reduce the risk of breast cancer recurrence.” Only 46.8% of those in agreement with the previous statement actually report eating at least 5 fruits and/or vegetables per day. With respect to exercise, 32.9% reported being unsure or in disagreement with the statement “Engaging in regular physical activity will reduce the risk of breast cancer recurrence.” Only 68.5% of those in agreement with the previous statement report any physical activity in the past 30 days.
Many breast cancer survivors do not appear to be aware of the benefits of diet and exercise. Further, a large proportion of those who are aware of the benefits do not adapt a healthy diet and exercise as part of their lifestyle. A majority of these survivors see a primary care physician, which we believe is the best venue to bridge this education gap. It is apparent by the pattern our data shows that more needs to be done to educate breast cancer survivors about the benefits of exercise and fruit and vegetable intake. Steps need to be taken to ensure that those who are educated also remain motivated to engage in a healthy lifestyle with the hopes of avoiding breast cancer recurrence.
PMCID: PMC2914278  PMID: 20697528
breast cancer; relapse rate; exercise; diet
11.  Targeting DNA Damage and Repair by Curcumin 
Curcumin is a compound with anti-tumor effects in a tolerable dose. A recent paper by Rowe et al described that curcumin induced DNA damage in triple negative breast cancer cells and regulated BRCA1 protein expression and modification.1 Related research and potential use of curcumin will be discussed in this article.
PMCID: PMC2914279  PMID: 20697527
curcumin; DNA damage; breast cancer cells

Results 1-11 (11)