Breast Cancer Lecture 4.doc

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Anatomy and Cell Biology
Anatomy and Cell Biology 4461B
Geordie Shepherd

LP Lecture 7: Breast Cancer Detecting Breast Cancer • Advent of imaging technologies such as mammography and MRI Education of women in the area of self-examination • • Earlier detection means that more cancers are found at less aggressive, non-metastatic stage • Cellular MRIs also possible Known Risk Factors • Age • Obesity • Alcohol intake • Lifetime estrogen exposure • Mammographic density • Genetic predisposition; 20% associated with familial history Predicting Breast Cancer • BRCA1 and BRCA1 mutations • >1000 mutations identified • Considered to be tumor suppressor genes • One inherited defective copy is sufficient for predisposition • Loss of wild type allele required for tumorigenesis • Account for 2-5% of cancers • Tumors arise early and tend to be highly aggressive Also associated with ovarian cancer • • 20% of women who carry BRCA1 mutations will develop breast cancer by age forty, 51% by fifty and 87% by age sixty • BRCA1 and BRCA2 • On chromosomes 17 and 13, respectively • Large mutlfunctional proteins • Homologous recombination • DNA damage response • Cell cycle checkpoint control • Chromatin modification • Centrosome duplication • X chromosome inactivation • Caretaker genes that ensure genomic stability Genetic Testing • Testing to detect mutations in BRCA1 and BRCA2 • Expensive and controversial • Test to measure BRCA protein function • Molecular characterization • cDNA microarrays followed by IHC • 4 biologically distinct subtypes • Luminal A - ER+/PR+, HER2-, low Ki67 • Luminal B - ER+/PR+, HER2+, or HER2- with high Ki67 • Triple Negative/Basal-like - ER-/PR-, cytokeratin 5/6+ and HER1+ • HER2+ - ER-, PR-, HER2+ • Basal and Her2 signatures indicate poor prognosis • 21 gene RT-PCR assay to determine a “likeliness of recurrence” score • Mammaprint: 70 gene prognostic kit Identifying the Seed • Cancer Stem Cells • Putative breast cancer stem cells defined • Self renew and differentiate into heterogenous tumor • Are these the cells to attack? Targeted Cancer Therapies • Usually used as an adjuvant or neoadjuvant therapy • Adjuvant therapy - prevent recurrence of eradicating micrometastases • Treatment is systemic • Chemotherapy • Endocrine treatment • Anti-HER2 therapy Anti-Hormone Therapy • Specific markers are routinely used to predict response to therapy and guide treatment planning • Anti-hormone therapies in breast cancer with tamoxifen and aromatase inhibitors repre- sent the first targeted therapy in oncology • Estrogen
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