Atypical hyperplasia of the breast: Clinical cases and management strategies.

Atypical hyperplasia of the breast is a histopathologic lesion identified incidentally on image-guided breast biopsy. It is associated with a substantial increase in lifetime risk for breast cancer. Clinicians should counsel women with atypical hyperplasia regarding risk-reducing strategies, which include preventive endocrine therapy options, enhanced surveillance imaging, and lifestyle modifications. In this review, we describe 5 different but common clinical case scenarios for atypical hyperplasia of the breast and review management strategies for each scenario.

Association Between Lifestyle Changes, Mammographic Breast Density, and Breast Cancer.

In screening for breast cancer (BC), mammographic breast density (MBD) is a powerful risk factor that increases breast carcinogenesis and synergistically reduces the sensitivity of mammography. It also reduces specificity of lesion identification, leading to recalls, additional testing, and delayed and later-stage diagnoses, which result in increased health care costs. These findings provide the foundation for dense breast notification laws and lead to the increase in patient and provider interest in MBD. However, unlike other risk factors for BC, MBD is dynamic through a woman's lifetime and is modifiable. Although MBD is known to change as a result of factors such as reproductive history and hormonal status, few conclusions have been reached for lifestyle factors such as alcohol, diet, physical activity, smoking, body mass index (BMI), and some commonly used medications. Our review examines the emerging evidence for the association of modifiable factors on MBD and the influence of MBD on BC risk. There are clear associations between alcohol use and menopausal hormone therapy and increased MBD. Physical activity and the Mediterranean diet lower the risk of BC without significant effect on MBD. Although high BMI and smoking are known risk factors for BC, they have been found to decrease MBD. The influence of several other factors, including caffeine intake, nonhormonal medications, and vitamins, on MBD is unclear. We recommend counseling patients on these modifiable risk factors and using this knowledge to help with informed decision making for tailored BC prevention strategies.

Local Recurrence of Invasive Secretory Breast Carcinoma in a Gravid Patient Post-Mastectomy.

This is a case of locally recurrent invasive secretory carcinoma of the breast during pregnancy, detected as a palpable mass in the reconstructed right breast of a 32-year-old female at 24 weeks gestation. The patient was initially diagnosed with secretory carcinoma 8 years prior, for which she underwent nipple sparing mastectomy followed by adjuvant chemotherapy and endocrine therapy. Due to pregnancy, the recurrence was treated initially with conservative excision alone, followed by definitive management postpartum which included wide local excision, sentinel lymph node biopsy and adjuvant chest wall radiation. Secretory carcinoma of the breast is a rare cancer with a predilection for young age and indolent course. This case report describes an unusual case of recurrent secretory carcinoma, of interest due to both its diagnosis during pregnancy, and its recurrence after nipple sparing mastectomy.

Breast cancer risk evaluation for the primary care physician.

Primary care physicians are typically the frontline clinicians who assess female patients for their risk of breast cancer, doing so by using a combination of risk algorithms and collecting personal and family medical histories. Patients found to be at increased risk of breast cancer, defined as > 20% overall lifetime risk, are candidates for enhanced screening. This review notes risk factors, determinants of risk, and a systematic approach for primary care physicians to assess and manage patients at risk of breast cancer.

Identifying women with increased risk of breast cancer and implementing risk-reducing strategies and supplemental imaging.

Breast cancer (BC) is the second most common cancer in women, affecting 1 in 8 women in the United States (12.5%) in their lifetime. However, some women have a higher lifetime risk of BC because of genetic and lifestyle factors, mammographic breast density, and reproductive and hormonal factors. Because BC risk is variable, screening and prevention strategies should be individualized after considering patient-specific risk factors. Thus, health care professionals need to be able to assess risk profiles, identify high-risk women, and individualize screening and prevention strategies through a shared decision-making process. In this article, we review the risk factors for BC, risk-assessment models that identify high-risk patients, and preventive medications and lifestyle modifications that may decrease risk. We also discuss the benefits and limitations of various supplemental screening methods.

Cloning and characterization of the promoter region of human focal adhesion kinase gene: nuclear factor kappa B and p53 binding sites.

Focal adhesion kinase (FAK) gene encodes focal adhesion kinase that localizes at contact points of cells with extracellular matrix. It was shown that FAK expression is increased in a variety of malignancies, both at early and advanced stages of tumorigenesis. To understand mechanisms of FAK gene expression and regulation, we cloned and characterized the 5' promoter region of the FAK gene. The 1.2-kb fragment with FAK promoter was placed upstream of the luciferase reporter gene in a pGL3-Basic vector and transfected into different cell lines. Endogenous high-FAK-expressing cell lines showed high levels of luciferase activity in contrast to low-FAK-expressing cells, indicating on transcriptional level of FAK regulation. Serial deletion constructs revealed that a approximately 600 base pair region (-564 to +47) is required for the maximal FAK promoter activity. The 5'-flanking region of FAK is GC-rich and contains several potential transcription factor binding sites, including two NF-kappa B and p53 binding sites. Inhibition of NF-kappa B with NF-kappa B super-repressor decreased FAK luciferase activity. Induction with TNF-alpha increased luciferase activity confirming a role of NF-kappa B transcription factor in the FAK transcriptional activation. The binding of NF-kappa B and p53 transcription factors to the FAK promoter region was demonstrated by electrophoretic mobility shift assay (EMSA). Cotransfection of NF-kappa B and p53 plasmids with FAK promoter luciferase constructs demonstrate induction and inhibition, respectively, of FAK luciferase activity. The results provide a molecular basis for analysis of FAK transcriptional regulation.

Simultaneous inhibition of focal adhesion kinase and SRC enhances detachment and apoptosis in colon cancer cell lines.

Focal adhesion kinase (FAK) and Src have been shown to be overexpressed in colon cancer. We have studied the role of these two kinases in resistance to apoptosis. Adenovirus-containing FAK-CD (Ad-FAK-CD), a dominant-negative, COOH-terminal portion of FAK, was used to inhibit FAK and cause apoptosis. Colon cancer cell lines were more resistant to Ad-FAK-CD-induced detachment and apoptosis than the breast cancer cell line, BT474. Colon cancer cell lines overexpressed highly active Src and FAK. Ad-FAK-CD-induced apoptosis was significantly increased by PP2, an inhibitor of Src family kinases. Activation of caspase-3, down-regulation of FAK, and Src and AKT activities were demonstrated in Ad-FAK-CD + PP2-treated colon cancer cells undergoing apoptosis. The results suggest that FAK and Src are both important survival factors, playing a role in protecting colon cancer cell lines from Ad-FAK-CD-induced apoptosis. Dual inhibition of these kinases may be important for therapies designed to enhance the apoptosis in colon cancers.