Accession Number : ADA487462


Title :   Breast Cancer Lymphatic Dissemination - Influence of Estrogen and Progesterone


Descriptive Note : Annual summary, 1 Mar 2007-28 Feb 2008


Corporate Author : COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO


Personal Author(s) : Harrell, Joshua C


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a487462.pdf


Report Date : Mar 2008


Pagination or Media Count : 30


Abstract : Breast cancers commonly spread to lymph nodes (LNs). If the primary tumors are estrogen receptor (ER) and/or progesterone receptor (PR) positive, then the likelihood that LN metastases express receptors exceeds 80%. We developed metastasis models using ZsGreen labeled MCF-7 and T47D human breast cancer cells. Tumors were tracked in living mice by whole-body imaging, and macrometastases or micrometastases were detected by intravital imaging or fluorescence microscopy. Tumor growth was estrogen dependent. To determine if the LN microenvironment alters estrogen-dependent gene expression, we developed a unique model to identify estradiol regulated genes in ER+ breast tumors and LN metastases. Fluorescent ER+ MCF-7 tumors were grown in ovariectomized nude mice supplemented with estradiol. Once axillary LN metastasis arose, estradiol was withdrawn (EWD), for 1 or 4 weeks, or continued, to assess estradiol responsiveness. On EWD, proliferation rates fell similarly in tumors and LN metastases. However, estradiol-dependent ER down-regulation and PR induction were deficient in LN metastases, indicating that ER transcriptional activity was altered in the LN. Cancer cells from estradiol treated and EWD primary tumors and matched LN metastases were isolated by laser capture microdissection. Global gene expression profiling identified transcripts that were regulated by the tissue microenvironment, by hormones, or by both. Interestingly, numerous genes that were estradiol regulated in tumors lost estradiol sensitivity or were regulated in the opposite direction by estradiol in LN metastases. We propose that the LN microenvironment alters estradiol signaling and contributes to antiestrogen resistance.


Descriptors :   *METASTASIS , *LYMPH NODES , *BREAST CANCER , GENES , PROTEINS , RECEPTOR SITES(PHYSIOLOGY)


Subject Categories : Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE